dbSNP rs121913395: CTNNB1:p.Ala21Thr (chr3-41224573-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001904.4(CTNNB1):c.61G>A(p.Ala21Thr) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
NM_001904.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the CTNNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 3.846 (above the threshold of 3.09). Trascript score misZ: 5.712 (above the threshold of 3.09). GenCC associations: The gene is linked to severe intellectual disability-progressive spastic diplegia syndrome, exudative vitreoretinopathy, exudative vitreoretinopathy 7.

BP4

Computational evidence support a benign effect (MetaRNN=0.26455465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4 link	c.61G>A	p.Ala21Thr	missense_variant	Exon 3 of 15	ENST00000349496.11	NP_001895.1	P35222A0A024R2Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11 link	c.61G>A	p.Ala21Thr	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5		P35222
CTNNB1	ENST00000645982.1 link	c.61G>A	p.Ala21Thr	missense_variant	Exon 3 of 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

Jul 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with CTNNB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 21 of the CTNNB1 protein (p.Ala21Thr). ClinVar contains an entry for this variant (Variation ID: 376224). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

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

Benign

0.14

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.011

MetaRNN

Benign

0.26

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

-1.1

MutationAssessor

Benign

0.34

N;.;N;.;N;N;N;N;N;.;N;N;.;.;N;N;N;.;.;.;.;N;N;.;.;.;N;.;.;N;N;.;N;.;N;.;N;N;N;N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.45

.;N;.;.;N;.;.;.;N;.;N;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N

REVEL

Benign

0.15

Sift

Benign

0.098

.;T;.;.;T;.;.;.;T;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;T

Sift4G

Benign

0.14

.;T;.;.;T;.;.;.;T;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;T

Polyphen

0.036

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

0.49, 0.48, 0.49, 0.49, 0.48

MutPred

0.25

Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;.;.;.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);.;Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);Gain of phosphorylation at A21 (P = 0.0501);

MVP

0.61

MPC

1.1

ClinPred

0.65

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.15

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over