2-47373967-T-C

Position:

chr2-47373967-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_002354.3(EPCAM):c.344T>C(p.Met115Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,613,628 control chromosomes in the GnomAD database, including 193,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 27738 hom., cov: 31)

Exomes 𝑓: 0.47 ( 166258 hom. )

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0500

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 -18 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=3.3098158E-6).

BP6

Variant 2-47373967-T-C is Benign according to our data. Variant chr2-47373967-T-C is described in ClinVar as [Benign]. Clinvar id is 183700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47373967-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.344T>C	p.Met115Thr	missense_variant	3/9	ENST00000263735.9	NP_002345.2	P16422

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9 link	c.344T>C	p.Met115Thr	missense_variant	3/9	1	NM_002354.3	ENSP00000263735.4		P16422

Frequencies

GnomAD3 genomes

AF:

0.577

AC:

87547

AN:

151766

Hom.:

27689

Cov.:

show subpopulations

Gnomad AFR

AF:

0.831

Gnomad AMI

AF:

0.354

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.363

Gnomad EAS

AF:

0.817

Gnomad SAS

AF:

0.498

Gnomad FIN

AF:

0.591

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.526

GnomAD3 exomes

AF:

0.513

AC:

129014

AN:

251424

Hom.:

35775

AF XY:

0.501

AC XY:

68033

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.842

Gnomad AMR exome

AF:

0.472

Gnomad ASJ exome

AF:

0.363

Gnomad EAS exome

AF:

0.832

Gnomad SAS exome

AF:

0.481

Gnomad FIN exome

AF:

0.596

Gnomad NFE exome

AF:

0.436

Gnomad OTH exome

AF:

0.464

GnomAD4 exome

AF:

0.467

AC:

683281

AN:

1461744

Hom.:

166258

Cov.:

AF XY:

0.466

AC XY:

338676

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.849

Gnomad4 AMR exome

AF:

0.474

Gnomad4 ASJ exome

AF:

0.368

Gnomad4 EAS exome

AF:

0.790

Gnomad4 SAS exome

AF:

0.480

Gnomad4 FIN exome

AF:

0.592

Gnomad4 NFE exome

AF:

0.438

Gnomad4 OTH exome

AF:

0.496

GnomAD4 genome

AF:

0.577

AC:

87649

AN:

151884

Hom.:

27738

Cov.:

AF XY:

0.582

AC XY:

43171

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.831

Gnomad4 AMR

AF:

0.494

Gnomad4 ASJ

AF:

0.363

Gnomad4 EAS

AF:

0.816

Gnomad4 SAS

AF:

0.498

Gnomad4 FIN

AF:

0.591

Gnomad4 NFE

AF:

0.442

Gnomad4 OTH

AF:

0.525

Alfa

AF:

0.461

Hom.:

42037

Bravo

AF:

0.580

TwinsUK

AF:

0.446

AC:

1654

ALSPAC

AF:

0.435

AC:

1676

ESP6500AA

AF:

0.828

AC:

3649

ESP6500EA

AF:

0.433

AC:

3722

ExAC

AF:

0.520

AC:

63080

Asia WGS

AF:

0.658

AC:

2287

AN:

3478

EpiCase

AF:

0.422

EpiControl

AF:

0.412

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27153395, 20683652, 22322561) -

Congenital diarrhea 5 with tufting enteropathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Lynch syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

IntelligeneCG

Aug 18, 2017

- -

Lynch syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2013

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.0039

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.018

.;T;T

MetaRNN

Benign

0.0000033

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.4

.;N;.

PrimateAI

Benign

0.31

PROVEAN

Benign

2.2

N;N;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.020

MPC

0.013

ClinPred

0.0024

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.36

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