3-41224646-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP5

The NM_001904.4(CTNNB1):c.134C>T(p.Ser45Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S45P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
NM_001904.4 missense

Scores

Clinical Significance

Pathogenic; other no assertion criteria provided P:2O:2

Conservation

PhyloP100: 7.91

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001904.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-41224645-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17589.Status of the report is no_assertion_criteria_provided, 0 stars.

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.

PP5

Variant 3-41224646-C-T is Pathogenic according to our data. Variant chr3-41224646-C-T is described in ClinVar as [Pathogenic, other]. Clinvar id is 17588.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4 link	c.134C>T	p.Ser45Phe	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.134C>T	p.Ser45Phe	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5		P35222
CTNNB1	ENST00000645982.1 link	c.134C>T	p.Ser45Phe	missense_variant	Exon 3 of 16			ENSP00000494845.1		P35222

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:2Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Gallbladder cancer

Pathogenic:1

Oct 30, 2020

Institute of Medical Sciences, Banaras Hindu University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hepatocellular carcinoma

Pathogenic:1

Jul 08, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nephroblastoma

Other:1

May 01, 2016

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: other

Review Status: no assertion criteria provided

Collection Method: clinical testing

- 2: Mutations in members of targetable cancer pathways, gene families, or functional groups, regardless of tumor type;

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

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

Pathogenic

0.86

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

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

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.74

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.6

M;.;M;.;M;M;M;M;M;.;M;M;.;.;M;M;M;.;.;.;.;M;M;.;.;.;M;.;.;M;M;.;M;.;M;.;M;M;M;M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.8

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

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.81, 0.81, 0.81, 0.81, 0.79

MutPred

0.30

Loss of glycosylation at S45 (P = 0.0113);.;Loss of glycosylation at S45 (P = 0.0113);.;Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);.;Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);.;.;Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);.;.;.;.;Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);.;Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);.;Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);.;Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);Loss of glycosylation at S45 (P = 0.0113);

MVP

0.87

MPC

2.4

ClinPred

0.99

GERP RS

5.9

Varity_R

0.83

gMVP

0.87

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