rs1057519380

Variant names:

• chr3-41239137-C-CTAGCTATCGTTCTTTT
• rs1057519380
• NM_001904.4:c.2142_2157dupTAGCTATCGTTCTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_001904.4(CTNNB1):​c.2142_2157dupTAGCTATCGTTCTTTT​(p.His720fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 frameshift, stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.889
• Publications: 3 publications found

Genes affected

CTNNB1 (HGNC:2514): (catenin beta 1) The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

CTNNB1 Gene-Disease associations (from GenCC):

• exudative vitreoretinopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• severe intellectual disability-progressive spastic diplegia syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• exudative vitreoretinopathy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PP5: Variant 3-41239137-C-CTAGCTATCGTTCTTTT is Pathogenic according to our data. Variant chr3-41239137-C-CTAGCTATCGTTCTTTT is described in ClinVar as Pathogenic. ClinVar VariationId is 225172.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.2142_2157dupTAGCTATCGTTCTTTT	p.His720fs	frameshift_variant, stop_gained	Exon 15 of 15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.2142_2157dupTAGCTATCGTTCTTTT	p.His720fs	frameshift_variant, stop_gained	Exon 15 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.2142_2157dupTAGCTATCGTTCTTTT	p.His720fs	frameshift_variant, stop_gained	Exon 15 of 16			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.*58_*73dupTAGCTATCGTTCTTTT		non_coding_transcript_exon_variant	Exon 15 of 16			ENSP00000520353.1
CTNNB1	ENST00000715152.1	n.*58_*73dupTAGCTATCGTTCTTTT		3_prime_UTR_variant	Exon 15 of 16			ENSP00000520353.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Exudative vitreoretinopathy 1 Pathogenic:1

Apr 01, 2016

Leeds Vision Research Group, University of Leeds

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Exudative vitreoretinopathy 7 Pathogenic:1

Aug 15, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.89
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519380; hg19: chr3-41280628;