3-41224073-C-G

Position:

chr3-41224073-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4BS2

The NM_001904.4(CTNNB1):c.5C>G(p.Ala2Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CTNNB1
NM_001904.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.59

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity CTNB1_HUMAN

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.3628875).

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4 linkuse as main transcript	c.5C>G	p.Ala2Gly	missense_variant	2/15	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.5C>G	p.Ala2Gly	missense_variant	2/15	1	NM_001904.4	ENSP00000344456.5		P35222
CTNNB1	ENST00000645982.1 linkuse as main transcript	c.5C>G	p.Ala2Gly	missense_variant	2/16			ENSP00000494845.1		P35222

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251364

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461482

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1362552). This variant has not been reported in the literature in individuals affected with CTNNB1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2 of the CTNNB1 protein (p.Ala2Gly). -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CTNNB1: PP2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.98

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

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.51

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

M_CAP

Benign

0.022

MetaRNN

Benign

0.36

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

1.2

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

REVEL

Benign

0.12

Sift

Benign

0.23

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

Sift4G

Benign

0.62

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

Polyphen

0.64

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

0.46, 0.45, 0.45, 0.49

MutPred

0.10

Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);Loss of glycosylation at T3 (P = 0.1324);

MVP

0.51

MPC

1.2

ClinPred

0.36

GERP RS

5.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.14

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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