rs62139669

Positions:

• chr2-47386560-T-C
• chr2-47386560-T-G

Variant summary

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

The ENST00000263735.9(EPCAM):​c.904-12T>C 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 0.0389 in 1,591,436 control chromosomes in the GnomAD database, including 1,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (124 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1281 hom.)
• Consequence: EPCAM ENST00000263735.9 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009840
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.60

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=-0.78).
• BP6: Variant 2-47386560-T-C is Benign according to our data. Variant chr2-47386560-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 258645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47386560-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPCAM	NM_002354.3	c.904-12T>C		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.904-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002354.3	ENSP00000263735	P1
EPCAM	ENST00000405271.5	c.988-12T>C		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000385476
EPCAM	ENST00000456133.5	c.988-12T>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5		ENSP00000410675

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 5221 AN: 152190 Hom.: 123 Cov.: 33

Gnomad AFR AF: 0.00825

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0617

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0566

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0430

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0402 AC: 9992 AN: 248810 Hom.: 260 AF XY: 0.0411 AC XY: 5538 AN XY: 134594

Gnomad AFR exome AF: 0.00627

Gnomad AMR exome AF: 0.0561

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.000437

Gnomad SAS exome AF: 0.0634

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0391

Gnomad OTH exome AF: 0.0392

GnomAD4 exome AF: 0.0394 AC: 56676 AN: 1439128 Hom.: 1281 Cov.: 27 AF XY: 0.0403 AC XY: 28826 AN XY: 716108

Gnomad4 AFR exome AF: 0.00530

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.0399

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.0648

Gnomad4 FIN exome AF: 0.0445

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0377

GnomAD4 genome AF: 0.0343 AC: 5222 AN: 152308 Hom.: 124 Cov.: 33 AF XY: 0.0361 AC XY: 2686 AN XY: 74484

Gnomad4 AFR AF: 0.00823

Gnomad4 AMR AF: 0.0616

Gnomad4 ASJ AF: 0.0378

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0570

Gnomad4 FIN AF: 0.0458

Gnomad4 NFE AF: 0.0430

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0396 Hom.: 34

Bravo AF: 0.0318

Asia WGS AF: 0.0220 AC: 78 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.6
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000098
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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: rs62139669; hg19: chr2-47613699;