Genetic Variant CTNNB1:p.Arg474* (chr3-41233763-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001904.4(CTNNB1):c.1420C>T(p.Arg474*) 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

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 2.02

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

exudative vitreoretinopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
severe intellectual disability-progressive spastic diplegia syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
exudative vitreoretinopathy 7
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CTNNB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 3-41233763-C-T is Pathogenic according to our data. Variant chr3-41233763-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 559636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4 link	c.1420C>T	p.Arg474*	stop_gained	Exon 9 of 15	ENST00000349496.11	NP_001895.1	P35222A0A024R2Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTNNB1	ENST00000349496.11 link	c.1420C>T	p.Arg474*	stop_gained	Exon 9 of 15	1	NM_001904.4	ENSP00000344456.5	P35222
CTNNB1	ENST00000645982.1 link	c.1420C>T	p.Arg474*	stop_gained	Exon 9 of 16			ENSP00000494845.1	P35222
CTNNB1	ENST00000715152.1 link	n.1420C>T		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000520353.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Severe intellectual disability-progressive spastic diplegia syndrome

Pathogenic:6

Genomics England Pilot Project, Genomics England

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 10, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 17, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated, PM6 moderated -

Sep 19, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000559636 /PMID: 25326669). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg474*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of CTNNB1-related conditions (PMID: 25326669, 27915094, 28333917). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 559636). For these reasons, this variant has been classified as Pathogenic. -

Oct 13, 2022

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28333917, 34758253, 27915094, 25326669, 27479843, 29786110, 31785789, 33004838) -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephalic primordial dwarfism, Alazami type

Pathogenic:1

Feb 28, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PP3, PP5 -

Developmental disorder

Pathogenic:1

Jan 04, 2022

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neurodevelopmental disorder

Pathogenic:1

Feb 24, 2021

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Medulloblastoma;C0206711:Pilomatrixoma;C0346629:Colorectal cancer;C0919267:Ovarian neoplasm;C2239176:Hepatocellular carcinoma;C3554449:Severe intellectual disability-progressive spastic diplegia syndrome;C4539767:Exudative vitreoretinopathy 7

Pathogenic:1

Molecular Genetics Lab, CHRU Brest

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.91

PhyloP100

2.0

Vest4

0.95, 0.95

GERP RS

4.6

PromoterAI

-0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over