2-47369510-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002354.3(EPCAM):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,552,862 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (11 hom.)
• Consequence: EPCAM NM_002354.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.04

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01036191).
• BP6: Variant 2-47369510-C-T is Benign according to our data. Variant chr2-47369510-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 127850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00185 (282/152282) while in subpopulation NFE AF= 0.0019 (129/68024). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3	c.5C>T	p.Ala2Val	missense_variant	1/9	ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPCAM	ENST00000263735.9	c.5C>T	p.Ala2Val	missense_variant	1/9	1	NM_002354.3	P1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00239 AC: 369 AN: 154334 Hom.: 3 AF XY: 0.00219 AC XY: 186 AN XY: 85076

Gnomad AFR exome AF: 0.000449

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000442

Gnomad FIN exome AF: 0.0000915

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00449

GnomAD4 exome AF: 0.00215 AC: 3005 AN: 1400580 Hom.: 11 Cov.: 31 AF XY: 0.00206 AC XY: 1424 AN XY: 692520

Gnomad4 AFR exome AF: 0.000422

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0259

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000506

Gnomad4 FIN exome AF: 0.0000926

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74460

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.0300

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00448 Hom.: 2

Bravo AF: 0.00188

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00101 AC: 4

ESP6500EA AF: 0.00173 AC: 14

ExAC AF: 0.00145 AC: 168

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	EPCAM: BS1 -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

True Health Diagnostics

Feb 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.085	T;D
Sift4G	Benign	0.29	T;D
Polyphen		0.98	D;.
Vest4		0.23
MVP		0.68
MPC		0.022
ClinPred		0.027	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.11
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201402370; hg19: chr2-47596649;