rs606231204

chr2-47377020-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002354.3(EPCAM):c.499dup(p.Gln167ProfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EPCAM NM_002354.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.568

Genes affected

EPCAM (HGNC:11529): (epithelial cell adhesion molecule) This gene encodes a carcinoma-associated antigen and is a member of a family that includes at least two type I membrane proteins. This antigen is expressed on most normal epithelial cells and gastrointestinal carcinomas and functions as a homotypic calcium-independent cell adhesion molecule. The antigen is being used as a target for immunotherapy treatment of human carcinomas. Mutations in this gene result in congenital tufting enteropathy. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47377020-T-TC is Pathogenic according to our data. Variant chr2-47377020-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 12774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3	c.499dup	p.Gln167ProfsTer21	frameshift_variant	5/9	ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPCAM	ENST00000263735.9	c.499dup	p.Gln167ProfsTer21	frameshift_variant	5/9	1	NM_002354.3	P1
EPCAM	ENST00000405271.5	c.583dup	p.Gln195ProfsTer21	frameshift_variant	6/10	5
EPCAM	ENST00000490733.1	n.348dup		non_coding_transcript_exon_variant	3/6	3
EPCAM	ENST00000456133.5	c.583dup	p.Gln195ProfsTer21	frameshift_variant, NMD_transcript_variant	6/11	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454666 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 724276

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital diarrhea 5 with tufting enteropathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The p.Gln167ProfsX21 variant in EPCAM has been reported in >20 homozygous individuals and 2 compound heterozygous individuals with congenital diahrrea with tufting enteropathy and and segregated with disease in at least 1 affected individuals from 1 family. It is thought to be a founder mutation in the Gulf communities (Al-Mayouf 2009 PMID: 19820410, Salomon 2011 PMID: 21315192, Salomon 2014 PMID: 24142340, AlMahamed 2017 PMID: 28361844). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 12774). Immunohistochemistry on cases and controls showed no staining for EPCAM on the intercellular memebrane in individuals homozygous for the variant (Salomon 2011 PMID: 21315192, Schnell 2013 PMID: 23462293, Alfares 2017 PMID: 28454995). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 167 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the EPCAM gene is an established disease mechanism in autosomal recessive congenital diahrrea with tufting enteropathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital diahrrea with tufting enteropathy. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PP1, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 08, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	May 02, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2021

Published functional studies demonstrate a damaging effect (Schnell et al., 2013); Not observed in large population cohorts (Lek et al., 2016); Frameshift 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; This variant is associated with the following publications: (PMID: 19820410, 21315192, 23462293, 28361844, 24142340, 28454995, 30202406, 30461124, 31462756, 32483295, 32735948) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs606231204; hg19: chr2-47604159;