chr2-47386570-A-G

Variant names:

• chr2-47386570-A-G
• rs878854496
• NM_002354.3:c.904-2A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002354.3(EPCAM):​c.904-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000138 in 1,447,884 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• 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: 5.49
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.4751323 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.2, offset of 6, new splice context is: ttttcctgtttcggataaAGgag. Cryptic site results in inframe 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 2-47386570-A-G is Pathogenic according to our data. Variant chr2-47386570-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 239144.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3	c.904-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 8	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9	c.904-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 8	1	NM_002354.3	ENSP00000263735.4
EPCAM	ENST00000405271.5	c.988-2A>G		splice_acceptor_variant, intron_variant	Intron 9 of 9	5		ENSP00000385476.1
EPCAM	ENST00000456133.5	n.988-2A>G		splice_acceptor_variant, intron_variant	Intron 9 of 10	5		ENSP00000410675.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447884 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 720536

African (AFR) AF: 0.00 AC: 0 AN: 33250

American (AMR) AF: 0.00 AC: 0 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 84102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102146

Other (OTH) AF: 0.00 AC: 0 AN: 59838

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 04, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in EPCAM are known to be pathogenic (PMID: 24142340). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. While genomic deletion of EPCAM exon 9 has been reported to affect the expression of the MSH2 mRNA and cause Lynch syndrome (PMID: 22243433, 23264089), this splice site variant that likely disrupts the EPCAM protein is not expected to affect MSH2 expression. This sequence change affects an acceptor splice site in intron 8. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		5.5
GERP RS		5.4
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.89		Position offset: 2

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

Other links and lift over

dbSNP: rs878854496; hg19: chr2-47613709;