rs863224453

Positions:

• chr2-47385165-G-A
• chr2-47385165-G-C
• chr2-47385165-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_002354.3(EPCAM):​c.859-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPCAM NM_002354.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.50

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.046560846 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of 1, new splice context is: ttgtctttcttccactcaAGtta. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47385165-G-A is Pathogenic according to our data. Variant chr2-47385165-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216000.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPCAM	NM_002354.3	c.859-1G>A		splice_acceptor_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.859-1G>A		splice_acceptor_variant, intron_variant		1	NM_002354.3	ENSP00000263735.4
EPCAM	ENST00000405271.5	c.943-1G>A		splice_acceptor_variant, intron_variant		5		ENSP00000385476.1
EPCAM	ENST00000456133.5	n.943-1G>A		splice_acceptor_variant, intron_variant		5		ENSP00000410675.1
EPCAM	ENST00000490733.1	n.708-1G>A		splice_acceptor_variant, intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2021

This sequence change affects an acceptor splice site in intron 7 of the EPCAM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EPCAM are known to be pathogenic (PMID: 24142340, 28361844). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with EPCAM-related conditions. Deletions involving the 3’ region (minimally, exon 9) lead to transcriptional read-through from the EPCAM promoter into the adjacent MSH2 gene, resulting in hypermethylation of the MSH2 promoter and silencing of MSH2 expression, causing Lynch syndrome (PMID: 19098912, 19177550, 21309036). However, variants resulting in a loss-of-function of the EPCAM protein while leaving exon 9 intact are known to cause congenital tufting enteropathy (PMID: 24142340, 28361844). For these reasons, this variant has been classified as Likely Pathogenic for congenital tufting enteropathy. However, this variant is not likely to confer risk for Lynch syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.85	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 2
DS_AL_spliceai		0.97		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224453; hg19: chr2-47612304;