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	Fusion Gene Summary
	Fusion Gene Sample Information
	Fusion ORF Analysis
	Fusion Amino Acid Sequences
	Fusion Protein Functional Features
	Fusion Protein Structure
	pLDDT scores
	Ramachandran Plot of Fusion Protein Structure
	Fusion Protein-Protein Interaction
	Related drugs with this fusion protein
	Related disease with this fusion protein

Fusion Protein:ITGB6-CNOT2

Fusion Protein Summary

Fusion gene summary

Fusion partner gene information	Fusion gene name: ITGB6-CNOT2
	FusionPDB ID: 40571
	FusionGDB2.0 ID: 40571
		Hgene	Tgene
	Gene symbol	ITGB6	CNOT2
	Gene ID	3694	4848
	Gene name	integrin subunit beta 6	CCR4-NOT transcription complex subunit 2
	Synonyms	AI1H	CDC36\|HSPC131\|IDNADFS\|NOT2\|NOT2H
	Cytomap	2q24.2	12q15
	Type of gene	protein-coding	protein-coding
	Description	integrin beta-6integrin, beta 6	CCR4-NOT transcription complex subunit 2CCR4-associated factor 2negative regulator of transcription 2
	Modification date	20200313	20200313
	UniProtAcc	P18564	Q9NZN8
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000283249, ENST00000409872, ENST00000409967, ENST00000428609, ENST00000485635,	ENST00000551483, ENST00000548230, ENST00000229195, ENST00000418359,
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)	* DoF score	7 X 10 X 6=420	27 X 20 X 10=5400
	# samples	14	29
	** MAII score	log2(14/420*10)=-1.58496250072116 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0	log2(29/5400*10)=-4.21883460192326 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0
Context (manual curation of fusion genes in FusionPDB)	PubMed: ITGB6 [Title/Abstract] AND CNOT2 [Title/Abstract] AND fusion [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)	ITGB6(160964190)-CNOT2(70731169), # samples:2
Anticipated loss of major functional domain due to fusion event.	ITGB6-CNOT2 seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF. ITGB6-CNOT2 seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF. ITGB6-CNOT2 seems lost the major protein functional domain in Hgene partner, which is a IUPHAR drug target due to the frame-shifted ORF. ITGB6-CNOT2 seems lost the major protein functional domain in Tgene partner, which is a cell metabolism gene due to the frame-shifted ORF. ITGB6-CNOT2 seems lost the major protein functional domain in Tgene partner, which is a essential gene due to the frame-shifted ORF.

* DoF score (Degree of Frequency) = # partners X # break points X # cancer types
** MAII score (Major Active Isofusion Index) = log2(# samples/DoF score*10)

Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Partner	Gene	GO ID	GO term	PubMed ID
Hgene	ITGB6	GO:0033627	cell adhesion mediated by integrin	17158881
Hgene	ITGB6	GO:1901388	regulation of transforming growth factor beta activation	22278742
Tgene	CNOT2	GO:0000122	negative regulation of transcription by RNA polymerase II	14707134\|16712523

Fusion gene breakpoints across ITGB6 (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Fusion gene breakpoints across CNOT2 (3'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

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Fusion Gene Sample Information

Fusion gene information from FusionGDB2.0.

Fusion gene information from two resources (ChiTars 5.0 and ChimerDB 4.0)
* All genome coordinats were lifted-over on hg19.
* Click on the break point to see the gene structure around the break point region using the UCSC Genome Browser.

Source	Disease	Sample	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand
ChimerDB4	SARC	TCGA-DX-A6BG-01A	ITGB6	chr2	160964190	-	CNOT2	chr12	70731169	+
ChimerDB4	SARC	TCGA-DX-A7ES-01A	ITGB6	chr2	160964190	-	CNOT2	chr12	70731169	+

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Fusion ORF Analysis

Fusion information from ORFfinder translation from full-length transcript sequence from FusionPDB.

Henst

Tenst

Hgene

Hchr

Hbp

Hstrand

Tgene

Tchr

Tbp

Tstrand

Seq length
(transcript)

BP loci
(transcript)

Predicted start
(transcript)

Predicted stop
(transcript)

Seq length
(amino acids)

ENST00000409872

ITGB6

chr2

160964190

ENST00000229195

CNOT2

chr12

70731169

4328

2402

125

2413

762

ENST00000409872

ITGB6

chr2

160964190

ENST00000418359

CNOT2

chr12

70731169

4328

2402

125

2413

762

DeepORF prediction of the coding potential based on the fusion transcript sequence of in-frame fusion genes. DeepORF is a coding potential classifier based on convolutional neural network by comparing the real Ribo-seq data. If the no-coding score < 0.5 and coding score > 0.5, then the in-frame fusion transcript is predicted as being likely translated.

Henst	Tenst	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	No-coding score	Coding score
ENST00000409872	ENST00000229195	ITGB6	chr2	160964190	-	CNOT2	chr12	70731169	+	0.000330608	0.99966943
ENST00000409872	ENST00000418359	ITGB6	chr2	160964190	-	CNOT2	chr12	70731169	+	0.000330608	0.99966943

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Fusion Amino Acid Sequences

For individual full-length fusion transcript sequence from FusionPDB, we ran ORFfinder and chose the longest ORF among the all predicted ones.

>FusionGDB ID_FusionGDB isoform ID_FGname_Hgene_Hchr_Hbp_Henst_Tgene_Tchr_Tbp_Tenst_length(fusion AA) seq_BP

>40571_40571_1_ITGB6-CNOT2_ITGB6_chr2_160964190_ENST00000409872_CNOT2_chr12_70731169_ENST00000229195_length(amino acids)=762AA_BP=
MKRMGIELLCLFFLFLGRNDHVQGGCALGGAETCEDCLLIGPQCAWCAQENFTHPSGVGERCDTPANLLAKGCQLNFIENPVSQVEILKN
KPLSVGRQKNSSDIVQIAPQSLILKLRPGGAQTLQVHVRQTEDYPVDLYYLMDLSASMDDDLNTIKELGSRLSKEMSKLTSNFRLGFGSF
VEKPVSPFVKTTPEEIANPCSSIPYFCLPTFGFKHILPLTNDAERFNEIVKNQKISANIDTPEGGFDAIMQAAVCKEKIGWRNDSLHLLV
FVSDADSHFGMDSKLAGIVIPNDGLCHLDSKNEYSMSTVLEYPTIGQLIDKLVQNNVLLIFAVTQEQVHLYENYAKLIPGATVGLLQKDS
GNILQLIISAYEELRSEVELEVLGDTEGLNLSFTAICNNGTLFQHQKKCSHMKVGDTASFSVTVNIPHCERRSRHIIIKPVGLGDALELL
VSPECNCDCQKEVEVNSSKCHHGNGSFQCGVCACHPGHMGPRCECGEDMLSTDSCKEAPDHPSCSGRGDCYCGQCICHLSPYGNIYGPYC
QCDNFSCVRHKGLLCGGNGDCDCGECVCRSGWTGEYCNCTTSTDSCVSEDGVLCSGRGDCVCGKCVCTNPGASGPTCERCPTCGDPCNSK
RSCIECHLSAAGQAREECVDKCKLAGATISEEEDFSKDGSVSCSLQGENECLITFLITTDNEGKTIIHSINEKDCPKPPNIPMIMLGVSL

--------------------------------------------------------------

>40571_40571_2_ITGB6-CNOT2_ITGB6_chr2_160964190_ENST00000409872_CNOT2_chr12_70731169_ENST00000418359_length(amino acids)=762AA_BP=
MKRMGIELLCLFFLFLGRNDHVQGGCALGGAETCEDCLLIGPQCAWCAQENFTHPSGVGERCDTPANLLAKGCQLNFIENPVSQVEILKN
KPLSVGRQKNSSDIVQIAPQSLILKLRPGGAQTLQVHVRQTEDYPVDLYYLMDLSASMDDDLNTIKELGSRLSKEMSKLTSNFRLGFGSF
VEKPVSPFVKTTPEEIANPCSSIPYFCLPTFGFKHILPLTNDAERFNEIVKNQKISANIDTPEGGFDAIMQAAVCKEKIGWRNDSLHLLV
FVSDADSHFGMDSKLAGIVIPNDGLCHLDSKNEYSMSTVLEYPTIGQLIDKLVQNNVLLIFAVTQEQVHLYENYAKLIPGATVGLLQKDS
GNILQLIISAYEELRSEVELEVLGDTEGLNLSFTAICNNGTLFQHQKKCSHMKVGDTASFSVTVNIPHCERRSRHIIIKPVGLGDALELL
VSPECNCDCQKEVEVNSSKCHHGNGSFQCGVCACHPGHMGPRCECGEDMLSTDSCKEAPDHPSCSGRGDCYCGQCICHLSPYGNIYGPYC
QCDNFSCVRHKGLLCGGNGDCDCGECVCRSGWTGEYCNCTTSTDSCVSEDGVLCSGRGDCVCGKCVCTNPGASGPTCERCPTCGDPCNSK
RSCIECHLSAAGQAREECVDKCKLAGATISEEEDFSKDGSVSCSLQGENECLITFLITTDNEGKTIIHSINEKDCPKPPNIPMIMLGVSL

--------------------------------------------------------------

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Fusion Protein Functional Features

Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr2:160964190/chr12:70731169)
- FGviewer provides the online visualization of the retention search of the protein functional features across DNA, RNA, protein, and pathological levels.
- How to search
1. Put your fusion gene symbol.
2. Press the tab key until there will be shown the breakpoint information filled.
4. Go down and press 'Search' tab twice.
4. Go down to have the hyperlink of the search result.
5. Click the hyperlink.
6. See the FGviewer result for your fusion gene.

Main function of each fusion partner protein. (from UniProt)

Hgene	Tgene
ITGB6 P18564	CNOT2 Q9NZN8
FUNCTION: Integrin alpha-V:beta-6 (ITGAV:ITGB6) is a receptor for fibronectin and cytotactin (PubMed:17545607, PubMed:17158881). It recognizes the sequence R-G-D in its ligands (PubMed:17545607, PubMed:17158881). Internalisation of integrin alpha-V/beta-6 via clathrin-mediated endocytosis promotes carcinoma cell invasion (PubMed:17545607, PubMed:17158881). ITGAV:ITGB6 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:17158881). Integrin alpha-V:beta-6 (ITGAV:ITGB6) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation (PubMed:15184403, PubMed:22278742, PubMed:28117447). {ECO:0000269\|PubMed:15184403, ECO:0000269\|PubMed:17158881, ECO:0000269\|PubMed:17545607, ECO:0000269\|PubMed:22278742, ECO:0000269\|PubMed:28117447}.; FUNCTION: (Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for Coxsackievirus A9 and Coxsackievirus B1. {ECO:0000269\|PubMed:15194773, ECO:0000269\|PubMed:9426447}.; FUNCTION: (Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for Herpes simplex virus-1/HHV-1 (PubMed:24367260). {ECO:0000269\|PubMed:24367260}.	FUNCTION: Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Required for the CCR4-NOT complex structural integrity. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may specifically involve the N-Cor repressor complex containing HDAC3, NCOR1 and NCOR2. Involved in the maintenance of embryonic stem (ES) cell identity. {ECO:0000269\|PubMed:14707134, ECO:0000269\|PubMed:16712523, ECO:0000269\|PubMed:21299754, ECO:0000269\|PubMed:22367759}.

Retention analysis result of each fusion partner protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at
download page
* Minus value of BPloci means that the break pointn is located before the CDS.

- Retained protein feature among the 13 regional features.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

131_371

756.0

789.0

Domain

Note=VWFA

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

131_371

756.0

789.0

Domain

Note=VWFA

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

456_619

756.0

789.0

Region

Note=Cysteine-rich tandem repeats

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

456_619

756.0

789.0

Region

Note=Cysteine-rich tandem repeats

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

456_501

756.0

789.0

Repeat

Note=I

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

502_543

756.0

789.0

Repeat

Note=II

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

544_582

756.0

789.0

Repeat

Note=III

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

583_619

756.0

789.0

Repeat

Note=IV

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

456_501

756.0

789.0

Repeat

Note=I

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

502_543

756.0

789.0

Repeat

Note=II

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

544_582

756.0

789.0

Repeat

Note=III

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

583_619

756.0

789.0

Repeat

Note=IV

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

22_709

756.0

789.0

Topological domain

Extracellular

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

22_709

756.0

789.0

Topological domain

Extracellular

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

710_730

756.0

789.0

Transmembrane

Helical

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

710_730

756.0

789.0

Transmembrane

Helical

Tgene

CNOT2

chr2:160964190

chr12:70731169

ENST00000229195

437_540

258.3333333333333

541.0

Region

Note=Repressor domain

Tgene

CNOT2

chr2:160964190

chr12:70731169

ENST00000418359

437_540

258.3333333333333

541.0

Region

Note=Repressor domain

Tgene

CNOT2

chr2:160964190

chr12:70731169

ENST00000551483

437_540

192.0

Region

Note=Repressor domain

- Not-retained protein feature among the 13 regional features.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000283249

731_788

756.0

789.0

Topological domain

Cytoplasmic

Hgene

ITGB6

chr2:160964190

chr12:70731169

ENST00000409872

731_788

756.0

789.0

Topological domain

Cytoplasmic

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Fusion Protein Structures

PDB and CIF files of the predicted fusion proteins
* Here we show the 3D structure of the fusion proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format.

Fusion protein PDB link (fusion AA seq ID in FusionPDB)	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	AA seq	Len(AA seq)
PDB file >>>1534_ITGB6_160964190_CNOT2_70731169_ranked_0.pdb	ITGB6	160964190	160964190	ENST00000418359	CNOT2	chr12	70731169	+	MKRMGIELLCLFFLFLGRNDHVQGGCALGGAETCEDCLLIGPQCAWCAQENFTHPSGVGERCDTPANLLAKGCQLNFIENPVSQVEILKN KPLSVGRQKNSSDIVQIAPQSLILKLRPGGAQTLQVHVRQTEDYPVDLYYLMDLSASMDDDLNTIKELGSRLSKEMSKLTSNFRLGFGSF VEKPVSPFVKTTPEEIANPCSSIPYFCLPTFGFKHILPLTNDAERFNEIVKNQKISANIDTPEGGFDAIMQAAVCKEKIGWRNDSLHLLV FVSDADSHFGMDSKLAGIVIPNDGLCHLDSKNEYSMSTVLEYPTIGQLIDKLVQNNVLLIFAVTQEQVHLYENYAKLIPGATVGLLQKDS GNILQLIISAYEELRSEVELEVLGDTEGLNLSFTAICNNGTLFQHQKKCSHMKVGDTASFSVTVNIPHCERRSRHIIIKPVGLGDALELL VSPECNCDCQKEVEVNSSKCHHGNGSFQCGVCACHPGHMGPRCECGEDMLSTDSCKEAPDHPSCSGRGDCYCGQCICHLSPYGNIYGPYC QCDNFSCVRHKGLLCGGNGDCDCGECVCRSGWTGEYCNCTTSTDSCVSEDGVLCSGRGDCVCGKCVCTNPGASGPTCERCPTCGDPCNSK RSCIECHLSAAGQAREECVDKCKLAGATISEEEDFSKDGSVSCSLQGENECLITFLITTDNEGKTIIHSINEKDCPKPPNIPMIMLGVSL	762

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pLDDT score distribution

pLDDT score distribution of the predicted wild-type structures of two partner proteins from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.

ITGB6_pLDDT.png

CNOT2_pLDDT.png

pLDDT score distribution of the predicted fusion protein structures from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.

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Ramachandran Plot of Fusion Protein Structure

Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this fusion protein peptide.

Fusion AA seq ID in FusionPDB and their Ramachandran plots

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Fusion Protein-Protein Interaction

Go to ChiPPI (Chimeric Protein-Protein interactions) to see the chimeric PPI interaction in
ChiPPI page.

Protein-protein interactors with each fusion partner protein in wild-type from validated records (BIOGRID-3.4.160)

Gene

PPI interactors

Protein-protein interactors based on sequence similarity (STRING)

Gene	STRING network
ITGB6
CNOT2

- Retained interactions in fusion protein (protein functional feature from UniProt).

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Still interaction with

- Lost interactions due to fusion (protein functional feature from UniProt).

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Interaction lost with

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Related Drugs to ITGB6-CNOT2

Drugs used for this fusion-positive patient.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)

Hgene

Tgene

Drug

Source

PMID

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Related Diseases to ITGB6-CNOT2

Diseases that have this fusion gene.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)

Hgene

Tgene

Disease

Source

PMID

Diseases associated with fusion partners.
(DisGeNet 4.0)

Partner

Gene

Disease ID

Disease name

# pubmeds

Source