rs115283528

chr2-47379942-A-Gchr2-47379942-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_002354.3(EPCAM):c.831A>G(p.Ile277Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,570 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I277V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: EPCAM NM_002354.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00895828).
• BP6: Variant 2-47379942-A-G is Benign according to our data. Variant chr2-47379942-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 127851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00146 (222/152316) while in subpopulation SAS AF= 0.00228 (11/4828). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3	c.831A>G	p.Ile277Met	missense_variant	7/9	ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPCAM	ENST00000263735.9	c.831A>G	p.Ile277Met	missense_variant	7/9	1	NM_002354.3	P1
EPCAM	ENST00000405271.5	c.915A>G	p.Ile305Met	missense_variant	8/10	5
EPCAM	ENST00000490733.1	n.680A>G		non_coding_transcript_exon_variant	5/6	3
EPCAM	ENST00000456133.5	c.915A>G	p.Ile305Met	missense_variant, NMD_transcript_variant	8/11	5

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00217 AC: 543 AN: 249802 Hom.: 1 AF XY: 0.00230 AC XY: 311 AN XY: 135100

Gnomad AFR exome AF: 0.000805

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00806

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00269

Gnomad FIN exome AF: 0.00255

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00167 AC: 2439 AN: 1461254 Hom.: 7 Cov.: 32 AF XY: 0.00177 AC XY: 1289 AN XY: 726894

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00311

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74486

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00146

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	EPCAM: BP4 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 26, 2021	- -

EPCAM-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

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

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

True Health Diagnostics

Apr 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.044	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0090	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.74	P;P
Vest4		0.41
MVP		0.61
MPC		0.023
ClinPred		0.033	T
GERP RS		-0.51
Varity_R		0.045
gMVP		0.31

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

Other links and lift over

dbSNP: rs115283528; hg19: chr2-47607081;