3-41224630-A-C

Position:

• chr3-41224630-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_001904.4(CTNNB1):​c.118A>C​(p.Thr40Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 9.32

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 3 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 3-41224630-A-C is Pathogenic according to our data. Variant chr3-41224630-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376236.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4095713). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.118A>C	p.Thr40Pro	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.118A>C	p.Thr40Pro	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

Neoplasm 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	Benign	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	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	0.28
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;T;.;.;.;.;T;T;T;.;.;T;.;.;.;.;T;.;T;.;.;.;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	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	-0.96	T
MutationAssessor	Uncertain	2.1	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	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;N;.;.;.;D;.;N;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
REVEL	Benign	0.24
Sift	Uncertain	0.0040	.;D;.;.;T;.;.;.;D;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Uncertain	0.028	.;D;.;.;T;.;.;.;T;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Polyphen		0.021	B;.;B;.;B;B;B;B;B;.;B;B;.;.;B;B;B;.;.;.;.;B;B;.;.;.;B;.;.;B;B;.;B;.;B;.;B;B;B;B;B
Vest4		0.53, 0.53, 0.53, 0.53, 0.53
MutPred		0.15		Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;.;.;.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);
MVP		0.84
MPC		1.4
ClinPred		0.86	D
GERP RS		5.9
Varity_R		0.70
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519836; hg19: chr3-41266121;