rs200676965

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_002354.3(EPCAM):c.577A>G(p.Ile193Val) variant causes a missense change. The variant allele was found at a frequency of 0.000328 in 1,564,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I193T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7B:1

Conservation

PhyloP100: 5.33

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 Likely_benign. Variant got -1 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000334 (472/1412050) while in subpopulation NFE AF= 0.000427 (456/1066956). AF 95% confidence interval is 0.000395. There are 0 homozygotes in gnomad4_exome. There are 238 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3 linkuse as main transcript	c.577A>G	p.Ile193Val	missense_variant	6/9	ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EPCAM	ENST00000263735.9 linkuse as main transcript	c.577A>G	p.Ile193Val	missense_variant	6/9	1	NM_002354.3	P1
EPCAM	ENST00000405271.5 linkuse as main transcript	c.661A>G	p.Ile221Val	missense_variant	7/10	5
EPCAM	ENST00000490733.1 linkuse as main transcript	n.426A>G		non_coding_transcript_exon_variant	4/6	3
EPCAM	ENST00000456133.5 linkuse as main transcript	c.661A>G	p.Ile221Val	missense_variant, NMD_transcript_variant	7/11	5

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251104

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000388

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000334

AC:

472

AN:

1412050

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

238

AN XY:

705802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000427

Gnomad4 OTH exome

AF:

0.000204

GnomAD4 genome

AF:

0.000269

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000297

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 136027). This variant has not been reported in the literature in individuals affected with EPCAM-related conditions. This variant is present in population databases (rs200676965, gnomAD 0.04%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 193 of the EPCAM protein (p.Ile193Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The EPCAM p.Ile193Val variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200676965) and ClinVar (classified as uncertain significane by PreventionGenetics, Fulgent Genetics, Illumina and Invitae). The variant was identified in control databases in 60 of 282506 chromosomes at a frequency of 0.0002124 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 52 of 128920 chromosomes (freq: 0.000403), African in 7 of 24924 chromosomes (freq: 0.000281) and Latino in 1 of 35426 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Ile193 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Lynch syndrome 8

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 09, 2023	The EPCAM c.577A>G (p.Ile193Val) missense variant has a maximum subpopulation frequency of 0.040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2021

DNA sequence analysis of the EPCAM gene demonstrated a sequence change, c.577A>G, in exon 6 that results in an amino acid change, p.Ile193Val. This sequence change has been described in the gnomAD database with a frequency of 0.04% in the non-Finnish European sub-population (dbSNP rs200676965). The p.Ile193Val change affects a highly conserved amino acid residue located in a domain of the EPCAM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile193Val substitution. This sequence change does not appear to have been previously described in individuals with EPCAM-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ile193Val change remains unknown at this time. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

EPCAM-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

The EPCAM c.577A>G variant is predicted to result in the amino acid substitution p.Ile193Val. To our knowledge, this variant has not been reported in the literature in a patient with an EPCAM related disorder. This variant is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/136027/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.042

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.49

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.29

Sift

Benign

0.22

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.82

P;P

Vest4

0.77

MVP

0.65

MPC

0.020

ClinPred

0.073

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

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