2-47373890-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_002354.3(EPCAM):c.267G>C(p.Gln89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,614,118 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 22 hom. )

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.971

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 Benign. Variant got -11 ACMG points.

PM1

In a domain Thyroglobulin type-1 (size 72) in uniprot entity EPCAM_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_002354.3

BP4

Computational evidence support a benign effect (MetaRNN=0.013347268).

BP6

Variant 2-47373890-G-C is Benign according to our data. Variant chr2-47373890-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127848.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=1}. Variant chr2-47373890-G-C is described in Lovd as [Likely_benign]. Variant chr2-47373890-G-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00284 (433/152236) while in subpopulation NFE AF= 0.00503 (342/68018). AF 95% confidence interval is 0.00459. There are 3 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.267G>C	p.Gln89His	missense_variant	Exon 3 of 9	ENST00000263735.9	NP_002345.2	P16422

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9 link	c.267G>C	p.Gln89His	missense_variant	Exon 3 of 9	1	NM_002354.3	ENSP00000263735.4		P16422

Frequencies

GnomAD3 genomes

AF:

0.00285

AC:

433

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00503

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00272

AC:

684

AN:

251466

Hom.:

AF XY:

0.00284

AC XY:

386

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00452

AC:

6604

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00440

AC XY:

3198

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.00555

Gnomad4 OTH exome

AF:

0.00308

GnomAD4 genome

AF:

0.00284

AC:

433

AN:

152236

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

191

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00503

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.00292

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00258

AC:

313

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EPCAM: BP4, BS1, BS2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The EPCAM c.267G>C (p.Gln89His) variant causes a missense change involving a non-conserved nucleotide with 2/3 in silico tools (SNPs&GO and Mutation Taster not captured here due to low reliability index and p-value, respectively) predicting a "damaging" outcome. The variant has been observed in the large, broad control population, ExAC, with an allele frequency of 313/121362 (1/387, 2 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic EPCAM variant of 1/35211, suggesting this variant is likely a benign polymorphism. Multiple clinical diagnostic laboratories cite the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Dec 24, 2013

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 28, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jan 28, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 15, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome

Benign:1

Mar 11, 2015

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

EPCAM-related disorder

Benign:1

May 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

T;T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.33

.;T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.1

.;M;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.016

D;D;D

Sift4G

Uncertain

0.026

D;D;D

Polyphen

1.0

D;P;.

Vest4

0.37

MutPred

0.49

Gain of helix (P = 0.0164);.;.;

MVP

0.66

MPC

0.078

ClinPred

0.036

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.53

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