2-47369587-G-A

Variant names:

• chr2-47369587-G-A
• rs774722931
• NM_002354.3:c.76+6G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002354.3(EPCAM):​c.76+6G>A variant causes a splice region, 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 benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPCAM NM_002354.3 splice_region, intron
• Scores: Splicing: ADA: 0.001597
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.214
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19298172).

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.76+6G>A		splice_region 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.76+6G>A		splice_region intron	N/A	ENSP00000263735.4
	EPCAM	ENST00000419334.1	TSL:3	c.82G>A	p.Ala28Thr	missense	Exon 1 of 3	ENSP00000389028.1
	EPCAM	ENST00000405271.5	TSL:5	c.160+352G>A		intron	N/A	ENSP00000385476.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1435546 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711686

African (AFR) AF: 0.00 AC: 0 AN: 32792

American (AMR) AF: 0.00 AC: 0 AN: 39916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25456

East Asian (EAS) AF: 0.00 AC: 0 AN: 38780

South Asian (SAS) AF: 0.00 AC: 0 AN: 82176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101324

Other (OTH) AF: 0.00 AC: 0 AN: 59426

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.92
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.64	T
PhyloP100		-0.21
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.20	T
MutPred		0.19		Gain of sheet (P = 0.0266)
MVP		0.71
ClinPred		0.15	T
GERP RS		1.9
PromoterAI		0.066	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.094
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs774722931; hg19: chr2-47596726;