2-47378939-A-G

Variant names:

• chr2-47378939-A-G
• rs376155665
• NM_002354.3:c.556-14A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_002354.3(EPCAM):​c.556-14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000953 in 1,153,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004848776: Studies have shown that this intronic variant creates a new acceptor site within intron 5, which is predicted to create a framshift variant p.Tyr186PhefsX6. Studies have also shown that this variant causes loss of cell-surface EpCAM (Schnell 2013 PMID:23462293, Salomon 2014 PMID:24142340)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: EPCAM NM_002354.3 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: -0.0690
• Publications: 16 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), Ambry Genetics, G2P, Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004848776: Studies have shown that this intronic variant creates a new acceptor site within intron 5, which is predicted to create a framshift variant p.Tyr186PhefsX6. Studies have also shown that this variant causes loss of cell-surface EpCAM (Schnell 2013 PMID: 23462293, Salomon 2014 PMID: 24142340).; SCV006584105: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23462293).; SCV000287358: An experimental study using cells expressing the truncated protein (p.Tyr186Phefs*6) has shown that this truncated protein lacks the transmembrane domain of EPCAM, resulting in loss of cell-surface EPCAM protein, and reduced protein secretion in vitro (PMID: 23462293).; SCV005346954: Transcript analysis found this variant results in abnormal splicing (Salomon et al. 2013. PubMed ID: 24142340) and immunostaining found it results in a lack of cell surface expression (Schnell et al. 2013. PubMed ID: 23462293).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47378939-A-G is Pathogenic according to our data. Variant chr2-47378939-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 157603.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	NM_002354.3	MANE Select	c.556-14A>G		intron	N/A	NP_002345.2	P16422

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000263735.9	TSL:1 MANE Select	c.556-14A>G		intron	N/A	ENSP00000263735.4	P16422
	EPCAM	ENST00000405271.5	TSL:5	c.640-14A>G		intron	N/A	ENSP00000385476.1	B5MCA4
	EPCAM	ENST00000895681.1		c.556-14A>G		intron	N/A	ENSP00000565740.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152060 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000764 AC: 19 AN: 248832 AF XY: 0.0000964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000105 AC: 105 AN: 1001604 Hom.: 0 Cov.: 14 AF XY: 0.000104 AC XY: 54 AN XY: 518722

African (AFR) AF: 0.0000407 AC: 1 AN: 24592

American (AMR) AF: 0.0000227 AC: 1 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.000172 AC: 4 AN: 23258

East Asian (EAS) AF: 0.0000801 AC: 3 AN: 37442

South Asian (SAS) AF: 0.000118 AC: 9 AN: 76578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52950

Middle Eastern (MID) AF: 0.000234 AC: 1 AN: 4266

European-Non Finnish (NFE) AF: 0.000124 AC: 86 AN: 693402

Other (OTH) AF: 0.00 AC: 0 AN: 45018

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152060 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74260

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000215 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Congenital diarrhea 5 with tufting enteropathy (10)
3	-	-	not provided (3)
1	-	-	EPCAM-related disorder (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Lynch syndrome 8;C2750737:Congenital diarrhea 5 with tufting enteropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Uncertain	25
DANN	Benign	0.56
PhyloP100		-0.069
Mutation Taster		=40/60	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 1

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

Other links and lift over

dbSNP: rs376155665; hg19: chr2-47606078; COSMIC: COSV55393327; COSMIC: COSV55393327;