NM_002354.3:c.492-2A>G

Variant names:

• chr2-47377012-A-G
• rs606231281
• NM_002354.3:c.492-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002354.3(EPCAM):​c.492-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000696 in 1,437,652 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: EPCAM NM_002354.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.68
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital diarrhea 5 with tufting enteropathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.7, offset of 10, new splice context is: ttctttacggtgcacttcAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47377012-A-G is Pathogenic according to our data. Variant chr2-47377012-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 157604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002354.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	NM_002354.3	MANE Select	c.492-2A>G		splice_acceptor intron	N/A	NP_002345.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000263735.9	TSL:1 MANE Select	c.492-2A>G		splice_acceptor intron	N/A	ENSP00000263735.4
	EPCAM	ENST00000405271.5	TSL:5	c.576-2A>G		splice_acceptor intron	N/A	ENSP00000385476.1
	EPCAM	ENST00000456133.5	TSL:5	n.576-2A>G		splice_acceptor intron	N/A	ENSP00000410675.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437652 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 716990

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33032

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1089948

Other (OTH) AF: 0.00 AC: 0 AN: 59582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital diarrhea 5 with tufting enteropathy Pathogenic:2

Jul 05, 2024

Aleixo Muise Laboratory, Hospital For Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS1;PM2;PM3;PP1;PP3;PP4

Jul 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Sep 11, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.492-2A>G splice site variant in the EPCAM gene has been previously reported in the homozygous and compound heterozygous states in multiple individuals with congenital tufting enteropathy (Salomon et al., 2011; Salomon et al., 2014). This variant destroys the canonical splice acceptor site in intron 4, and is expected to cause abnormal gene splicing. Based on currently available evidence, we consider c.492-2A>G to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		4.7
GERP RS		5.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: -16
DS_AL_spliceai		0.96		Position offset: 2

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

Other links and lift over

dbSNP: rs606231281; hg19: chr2-47604151;