Variant 3-41224536-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001330729.2(CTNNB1):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
NM_001330729.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

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 links:

CTNNB1 (HGNC:):

CTNNB1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4 linkuse as main transcript	c.24G>A	p.Met8Ile	missense_variant	3/15	ENST00000349496.11	NP_001895.1	P35222A0A024R2Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11 linkuse as main transcript	c.24G>A	p.Met8Ile	missense_variant	3/15	1	NM_001904.4	ENSP00000344456.5		P35222
CTNNB1	ENST00000645982.1 linkuse as main transcript	c.24G>A	p.Met8Ile	missense_variant	3/16			ENSP00000494845.1		P35222

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

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

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.47

T;D;T;D;T;T;T;T;T;D;T;T;D;D;T;T;T;D;D;D;D;T;T;T;T;T;T;D;T;T;T;D;T;T;T;D;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;L;.;L;L;L;L;L;.;L;L;.;.;L;L;L;.;.;.;.;L;L;.;.;.;L;.;.;L;L;.;L;.;L;.;L;L;L;L;L

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.2

.;N;.;.;N;.;D;.;N;.;N;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N

REVEL

Benign

0.29

Sift

Pathogenic

0.0

.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D

Sift4G

Pathogenic

0.0

.;D;.;.;T;.;.;.;D;.;T;T;.;.;T;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;D

Polyphen

0.0020

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

0.65, 0.66, 0.64, 0.68, 0.87

MutPred

0.26

Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;.;.;.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);

MVP

0.93

MPC

1.2

ClinPred

0.87

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.53

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over