NM_002354.3:c.106G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1BP4_StrongBP6_ModerateBS1BS2

The NM_002354.3(EPCAM):c.106G>A(p.Val36Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,612,644 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 3 hom. )

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.317

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 -12 ACMG points.

PM1

In a chain Epithelial cell adhesion molecule (size 290) in uniprot entity EPCAM_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_002354.3

BP4

Computational evidence support a benign effect (MetaRNN=0.011849076).

BP6

Variant 2-47373492-G-A is Benign according to our data. Variant chr2-47373492-G-A is described in ClinVar as [Benign]. Clinvar id is 220544.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000986 (15/152064) while in subpopulation SAS AF= 0.00125 (6/4814). AF 95% confidence interval is 0.000542. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.106G>A	p.Val36Ile	missense_variant	Exon 2 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.106G>A	p.Val36Ile	missense_variant	Exon 2 of 9	1	NM_002354.3	ENSP00000263735.4		P16422

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000315

AC:

AN:

250914

Hom.:

AF XY:

0.000442

AC XY:

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00239

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000171

AC:

250

AN:

1460580

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

178

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00218

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EPCAM-related disorder

Benign:1

Oct 15, 2019

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

Benign

0.071

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.4

DANN

Benign

0.90

DEOGEN2

Benign

0.019

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.52

.;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

.;L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.50

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.032

B;B;.

Vest4

0.13

MVP

0.15

MPC

0.013

ClinPred

0.0078

GERP RS

0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.050

gMVP

0.40

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