rs114241106

Positions:

• chr2-47373452-T-A
• chr2-47373452-T-C

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.77-11T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00976 in 1,571,516 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (97 hom.)
• Consequence: EPCAM NM_002354.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01286
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.89

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 (BayesDel_noAF=-0.87).
• BP6: Variant 2-47373452-T-A is Benign according to our data. Variant chr2-47373452-T-A is described in ClinVar as [Benign]. Clinvar id is 137214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47373452-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00732 (1114/152224) while in subpopulation NFE AF= 0.011 (747/68022). AF 95% confidence interval is 0.0103. There are 9 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPCAM	NM_002354.3	c.77-11T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9	c.77-11T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002354.3	ENSP00000263735	P1

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1116 AN: 152106 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00307

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00810 AC: 1963 AN: 242328 Hom.: 11 AF XY: 0.00848 AC XY: 1115 AN XY: 131468

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.00848

Gnomad FIN exome AF: 0.00438

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.0100 AC: 14228 AN: 1419292 Hom.: 97 Cov.: 27 AF XY: 0.0101 AC XY: 7177 AN XY: 708394

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00531

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.00938

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.00732 AC: 1114 AN: 152224 Hom.: 9 Cov.: 32 AF XY: 0.00661 AC XY: 492 AN XY: 74434

Gnomad4 AFR AF: 0.00306

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.0103 Hom.: 1

Bravo AF: 0.00759

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	EPCAM: BS1, BS2 -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Dec 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.014
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.23
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: rs114241106; hg19: chr2-47600591; COSMIC: COSV104560662; COSMIC: COSV104560662;