3-41224980-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001904.4(CTNNB1):​c.268C>T​(p.Arg90*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
NM_001904.4 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.74
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-41224980-C-T is Pathogenic according to our data. Variant chr3-41224980-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 253000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41224980-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTNNB1NM_001904.4 linkc.268C>T p.Arg90* stop_gained Exon 4 of 15 ENST00000349496.11 NP_001895.1 P35222A0A024R2Q3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTNNB1ENST00000349496.11 linkc.268C>T p.Arg90* stop_gained Exon 4 of 15 1 NM_001904.4 ENSP00000344456.5 P35222
CTNNB1ENST00000645982.1 linkc.268C>T p.Arg90* stop_gained Exon 4 of 16 ENSP00000494845.1 P35222

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6
-
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 13, 2020
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 06, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 253000). This premature translational stop signal has been observed in individual(s) with neurodevelopmental disorder (PMID: 28191889, 33004838). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg90*) in the CTNNB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNNB1 are known to be pathogenic (PMID: 23033978, 24614104, 25326669, 26350204, 28575650). -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Sep 19, 2018
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Severe intellectual disability-progressive spastic diplegia syndrome Pathogenic:1
Apr 27, 2016
Center of Genomic medicine, Geneva, University Hospital of Geneva
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant in CTNNB1 was found in combination with an another variant in CAMTA1, in a patient with severe mental retardation, ataxia, microcephaly and epilepsy -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.93
D
Vest4
0.96, 0.96
GERP RS
3.7
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8

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

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

Other links and lift over

dbSNP: rs1369821061; hg19: chr3-41266471; COSMIC: COSV100846211; COSMIC: COSV100846211; API