2-47378939-A-G

Position:

chr2-47378939-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_002354.3(EPCAM):c.556-14A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000953 in 1,153,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

EPCAM
NM_002354.3 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: -0.0690

Variant links:

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]

EPCAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-47378939-A-G is Pathogenic according to our data. Variant chr2-47378939-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 157603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47378939-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3 linkuse as main transcript	c.556-14A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
EPCAM	ENST00000263735.9 linkuse as main transcript	c.556-14A>G	splice_polypyrimidine_tract_variant, intron_variant	1	NM_002354.3	P1
EPCAM	ENST00000405271.5 linkuse as main transcript	c.640-14A>G	splice_polypyrimidine_tract_variant, intron_variant	5
EPCAM	ENST00000456133.5 linkuse as main transcript	c.640-14A>G	splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5
EPCAM	ENST00000490733.1 linkuse as main transcript	n.405-14A>G	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000764

AC:

AN:

248832

Hom.:

AF XY:

0.0000964

AC XY:

AN XY:

134840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000105

AC:

105

AN:

1001604

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

518722

show subpopulations

Gnomad4 AFR exome

AF:

0.0000407

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.000172

Gnomad4 EAS exome

AF:

0.0000801

Gnomad4 SAS exome

AF:

0.000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital diarrhea 5 with tufting enteropathy

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 30, 2022	The c.556-14A>G variant in EPCAM has been reported in 10 individuals with congenital tufting enteropathy, at least 3 of which were homozygous or had additional variants in EPCAM (Schnell 2013 PMID: 23462293, Salomon 2014 PMID: 24142340, Bodian 2017 PMID: 28701297). One of these individuals had absence of EPCAM cell surface expression (Bodian 2017 PMID: 28701297). It segregated with disease in 2 affected family members from 2 families (Salomon 2014 PMID: 24142340, Bodian 2017 PMID: 28701297). It has also been identified in 0.02% (1/5192) of East Asian and 0.01% (1/15268) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 157603). Studies have shown that this intronic variant creates a new acceptor site within intron 5, which is predicted to create a framshift variant p.Tyr186PhefsX6. Studies have also shown that this variant causes loss of cell-surface EpCAM (Schnell 2013 PMID: 23462293, Salomon 2014 PMID: 24142340). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive congenital tufting enteropathy. ACMG/AMP Criteria applied: PM3, PS3, PP1_Moderate. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 17, 2019	This variant was identified as homozygous -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics Facility, Ludwig-Maximilians-Universität München	Dec 28, 2021	- -
Pathogenic, criteria provided, single submitter	research	ITMI	Oct 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 02, 2023	The EPCAM c.556-14A>G intronic change results in an A to G substitution at the -14 position of intron 5 of the EPCAM gene. Algorithms that predict the impact of sequence changes on splicing indicate that this change results in the creation of a splice acceptor site, which is predicted to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in multiple individuals with congenital tufting enteropathy in the homozygous and compound heterozygous state (PMID: 23462293, 24142340, 26684320, 27848944, 28701297, 30461124). This variant has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as pathogenic with respect to congenital tufting enteropathy and of uncertain significance with respect to Lynch syndrome since the evidence currently available is insufficient to determine the clinical significance of this variant with respect to Lynch syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Jul 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -

Lynch syndrome 8;C2750737:Congenital diarrhea 5 with tufting enteropathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2019

For these reasons, this variant has been classified as Pathogenic. In cDNA sequence analysis using patient-derived RNA, this variant resulted in a frameshift caused by abnormal splicing (PMID: 24142340). An experimental study using cells expressing the truncated protein (p.Tyr186Phefs*6) has shown that this truncated protein lacks the transmembrane domain of EPCAM, resulting in loss of cell-surface EPCAM protein, and reduced protein secretion in vitro (PMID: 23462293). This variant has been reported in multiple individuals affected with congenital tufting enteropathy (CTE)¬†(PMID: 23462293, 24142340, 28701297). ClinVar contains an entry for this variant (Variation ID: 157603). This variant is present in population databases (rs376155665, ExAC 0.01%). This sequence change falls in intron 5 of the EPCAM mRNA. It has been shown to affect mRNA splicing through the creation of new splice acceptor site, which causes a frameshift at codon 186 and creates a premature translational stop signal (p.Tyr186Phefs*6) (PMID: 23462293, 24142340). It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Uncertain

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.96

Position offset: 1

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