rs78608315

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002354.3(EPCAM):c.492-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,592,016 control chromosomes in the GnomAD database, including 908 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 78 hom., cov: 31)

Exomes 𝑓: 0.031 ( 830 hom. )

Consequence

EPCAM
NM_002354.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.02180

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.58

Variant links:

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]

EPCAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 2-47377009-T-C is Benign according to our data. Variant chr2-47377009-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 132761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47377009-T-C is described in Lovd as [Benign]. Variant chr2-47377009-T-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0247 (3759/152270) while in subpopulation NFE AF= 0.0368 (2503/68012). AF 95% confidence interval is 0.0356. There are 78 homozygotes in gnomad4. There are 1894 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 78 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3 linkuse as main transcript	c.492-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
EPCAM	ENST00000263735.9 linkuse as main transcript	c.492-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_002354.3	P1
EPCAM	ENST00000405271.5 linkuse as main transcript	c.576-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5
EPCAM	ENST00000456133.5 linkuse as main transcript	c.576-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5
EPCAM	ENST00000490733.1 linkuse as main transcript	n.341-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	3

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3760

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00565

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.0577

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0368

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0248

AC:

6237

AN:

251224

Hom.:

137

AF XY:

0.0249

AC XY:

3387

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00573

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00559

Gnomad FIN exome

AF:

0.0566

Gnomad NFE exome

AF:

0.0359

Gnomad OTH exome

AF:

0.0269

GnomAD4 exome

AF:

0.0306

AC:

44099

AN:

1439746

Hom.:

830

Cov.:

AF XY:

0.0299

AC XY:

21487

AN XY:

717844

show subpopulations

Gnomad4 AFR exome

AF:

0.00492

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0105

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.00604

Gnomad4 FIN exome

AF:

0.0539

Gnomad4 NFE exome

AF:

0.0349

Gnomad4 OTH exome

AF:

0.0266

GnomAD4 genome

AF:

0.0247

AC:

3759

AN:

152270

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1894

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00563

Gnomad4 AMR

AF:

0.0179

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0577

Gnomad4 NFE

AF:

0.0368

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0240

Hom.:

Bravo

AF:

0.0203

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0343

EpiControl

AF:

0.0340

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 08, 2013	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 01, 2015	- -

not specified

Benign:3

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

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30461124) -

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

-0.48

CADD

Benign

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.022

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over