chr3-41224631-C-T

Position:

• chr3-41224631-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_001904.4(CTNNB1):​c.119C>T​(p.Thr40Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CTNNB1. . Gene score misZ 3.846 (greater than the threshold 3.09). Trascript score misZ 5.712 (greater than threshold 3.09). GenCC has associacion of gene with severe intellectual disability-progressive spastic diplegia syndrome, exudative vitreoretinopathy, exudative vitreoretinopathy 7.
• PP5: Variant 3-41224631-C-T is Pathogenic according to our data. Variant chr3-41224631-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376240.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.119C>T	p.Thr40Ile	missense_variant	3/15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.119C>T	p.Thr40Ile	missense_variant	3/15	1	NM_001904.4	ENSP00000344456	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;T;D;T;D;D;D;D;D;T;D;D;.;T;D;D;D;T;.;T;T;D;D;.;.;.;D;T;.;D;D;T;D;.;D;T;D;D;D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M;.;M;.;M;M;M;M;M;.;M;M;.;.;M;M;M;.;.;.;.;M;M;.;.;.;M;.;.;M;M;.;M;.;M;.;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
REVEL	Benign	0.17
Sift	Uncertain	0.010	.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Benign	0.091	.;T;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Polyphen		0.84	P;.;P;.;P;P;P;P;P;.;P;P;.;.;P;P;P;.;.;.;.;P;P;.;.;.;P;.;.;P;P;.;P;.;P;.;P;P;P;P;P
Vest4		0.52, 0.51, 0.52, 0.51, 0.52
MutPred		0.23		Loss of glycosylation at T40 (P = 0.0071);.;Loss of glycosylation at T40 (P = 0.0071);.;Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);.;Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);.;.;Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);.;.;.;.;Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);.;Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);.;Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);.;Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);Loss of glycosylation at T40 (P = 0.0071);
MVP		0.55
MPC		1.4
ClinPred		0.93	D
GERP RS		5.9
Varity_R		0.37
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519837; hg19: chr3-41266122; COSMIC: COSV62689000; COSMIC: COSV62689000;