3-41234157-C-T

Position:

• chr3-41234157-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001904.4(CTNNB1):​c.1543C>T​(p.Arg515*) variant causes a stop gained change. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.12

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 (HGNC:):

ACMG classification

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 3-41234157-C-T is Pathogenic according to our data. Variant chr3-41234157-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41234157-C-T is described in Lovd as [Pathogenic]. Variant chr3-41234157-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.1543C>T	p.Arg515*	stop_gained	10/15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1543C>T	p.Arg515*	stop_gained	10/15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.1543C>T	p.Arg515*	stop_gained	10/16			ENSP00000494845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe intellectual disability-progressive spastic diplegia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 02, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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 (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as de novoo in similary affected individuals (PMID:23033978, 25326669). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Sep 21, 2017	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	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: 25326669, 31526516, 35719373, 35935366, 35599849, 23033978) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2022	This sequence change creates a premature translational stop signal (p.Arg515*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39655). This premature translational stop signal has been observed in individual(s) with intellectual disability syndrome (PMID: 23033978, 31526516). This variant is not present in population databases (gnomAD no frequency). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.97, 0.97, 0.97
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs397514554; hg19: chr3-41275648; COSMIC: COSV62688116; COSMIC: COSV62688116;