2-47377018-C-T

Position:

chr2-47377018-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000263735.9(EPCAM):c.496C>T(p.Leu166Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000748 in 1,604,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

EPCAM
ENST00000263735.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -0.0610

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15711522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPCAM	NM_002354.3 linkuse as main transcript	c.496C>T	p.Leu166Phe	missense_variant	5/9	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EPCAM	ENST00000263735.9 linkuse as main transcript	c.496C>T	p.Leu166Phe	missense_variant	5/9	1	NM_002354.3	ENSP00000263735	P1
EPCAM	ENST00000405271.5 linkuse as main transcript	c.580C>T	p.Leu194Phe	missense_variant	6/10	5		ENSP00000385476
EPCAM	ENST00000490733.1 linkuse as main transcript	n.345C>T		non_coding_transcript_exon_variant	3/6	3
EPCAM	ENST00000456133.5 linkuse as main transcript	c.580C>T	p.Leu194Phe	missense_variant, NMD_transcript_variant	6/11	5		ENSP00000410675

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251306

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000482

AC:

AN:

1452762

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

723436

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000634

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 02, 2021

This sequence change replaces leucine with phenylalanine at codon 166 of the EPCAM protein (p.Leu166Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs587780768, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with EPCAM-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

True Health Diagnostics

Nov 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.22

CADD

Benign

7.7

DANN

Uncertain

0.99

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.59

.;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.7

.;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.065

T;D

Sift4G

Benign

0.064

T;D

Polyphen

0.34

B;B

Vest4

0.43

MVP

0.49

MPC

0.013

ClinPred

0.17

GERP RS

0.69

Varity_R

0.37

gMVP

0.47

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