rs116429842

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002354.3(EPCAM):c.50C>A(p.Thr17Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,588,506 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 29 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 31 hom. )

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.913

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:

EPCAM (HGNC:):

EPCAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032449365).

BP6

Variant 2-47369555-C-A is Benign according to our data. Variant chr2-47369555-C-A is described in ClinVar as [Benign]. Clinvar id is 137216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00975 (1485/152232) while in subpopulation AFR AF= 0.0321 (1332/41558). AF 95% confidence interval is 0.0306. There are 29 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPCAM	NM_002354.3 linkuse as main transcript	c.50C>A	p.Thr17Lys	missense_variant	1/9	ENST00000263735.9	NP_002345.2	P16422

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9 linkuse as main transcript	c.50C>A	p.Thr17Lys	missense_variant	1/9	1	NM_002354.3	ENSP00000263735.4		P16422

Frequencies

GnomAD3 genomes

AF:

0.00974

AC:

1482

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00582

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.00214

AC:

434

AN:

202956

Hom.:

AF XY:

0.00164

AC XY:

182

AN XY:

110944

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.000338

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.0000580

Gnomad NFE exome

AF:

0.000245

Gnomad OTH exome

AF:

0.00157

GnomAD4 exome

AF:

0.00127

AC:

1827

AN:

1436274

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

803

AN XY:

712490

show subpopulations

Gnomad4 AFR exome

AF:

0.0353

Gnomad4 AMR exome

AF:

0.00283

Gnomad4 ASJ exome

AF:

0.000393

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000110

Gnomad4 FIN exome

AF:

0.0000200

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.00320

GnomAD4 genome

AF:

0.00975

AC:

1485

AN:

152232

Hom.:

Cov.:

AF XY:

0.00916

AC XY:

682

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0321

Gnomad4 AMR

AF:

0.00581

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.0116

ESP6500AA

AF:

0.0296

AC:

127

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00244

AC:

292

Asia WGS

AF:

0.00318

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Aug 12, 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.42

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.13

Sift

Benign

0.18

T;D

Sift4G

Benign

0.39

T;D

Polyphen

0.50

P;.

Vest4

0.46

MVP

0.44

MPC

0.093

ClinPred

0.025

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.075

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