rs1421

Positions:

• chr2-47386731-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002354.3(EPCAM):​c.*118T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 794,348 control chromosomes in the GnomAD database, including 6,859 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1096 hom., cov: 33)
  • Exomes 𝑓: 0.13 (5763 hom.)
• Consequence: EPCAM NM_002354.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0870

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=-0.77).
• BP6: Variant 2-47386731-T-C is Benign according to our data. Variant chr2-47386731-T-C is described in ClinVar as [Benign]. Clinvar id is 1275848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47386731-T-C is described in Lovd as [Benign]. Variant chr2-47386731-T-C is described in Lovd as [Likely_benign]. Variant chr2-47386731-T-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPCAM	NM_002354.3	c.*118T>C		3_prime_UTR_variant	9/9	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9	c.*118T>C		3_prime_UTR_variant	9/9	1	NM_002354.3	ENSP00000263735.4
EPCAM	ENST00000405271.5	c.*118T>C		3_prime_UTR_variant	10/10	5		ENSP00000385476.1
EPCAM	ENST00000456133.5	n.*118T>C		non_coding_transcript_exon_variant	10/11	5		ENSP00000410675.1
EPCAM	ENST00000456133.5	n.*118T>C		3_prime_UTR_variant	10/11	5		ENSP00000410675.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15822 AN: 152142 Hom.: 1098 Cov.: 33

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.0629

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.126 AC: 80730 AN: 642088 Hom.: 5763 Cov.: 9 AF XY: 0.123 AC XY: 42268 AN XY: 343418

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.0640

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.0562

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.104 AC: 15825 AN: 152260 Hom.: 1096 Cov.: 33 AF XY: 0.105 AC XY: 7808 AN XY: 74436

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.0636

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.107

Alfa AF: 0.123 Hom.: 724

Bravo AF: 0.101

Asia WGS AF: 0.113 AC: 394 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	This variant is associated with the following publications: (PMID: 30461124) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

EPCAM-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2022

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

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Jan 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.1
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1421; hg19: chr2-47613870; COSMIC: COSV55393300; COSMIC: COSV55393300;