chr2-47345224-G-C

Variant names:

• chr2-47345224-G-C
• rs17036526
• ENST00000405271.5:c.-149+1G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The ENST00000405271.5(EPCAM):​c.-149+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 152,102 control chromosomes in the GnomAD database, including 5,239 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (5239 hom., cov: 31)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: EPCAM ENST00000405271.5 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.634
• Publications: 8 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]

ENSG00000301821 (HGNC:):

EPCAM-DT (HGNC:52639): (EPCAM divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06413994 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of -25, new splice context is: gggGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000405271.5. 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-DT	NR_110207.1		n.-150C>G		upstream_gene	N/A
	EPCAM-DT	NR_110208.1		n.-150C>G		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000405271.5	TSL:5	c.-149+1G>C		splice_donor intron	N/A	ENSP00000385476.1
	EPCAM	ENST00000456133.5	TSL:5	n.-149+1G>C		splice_donor intron	N/A	ENSP00000410675.1
	ENSG00000301821	ENST00000782063.1		n.374-6751G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36882 AN: 151890 Hom.: 5224 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.225

GnomAD4 exome AF: 0.128 AC: 12 AN: 94 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 8 AN XY: 64

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.131 AC: 11 AN: 84

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.243 AC: 36941 AN: 152008 Hom.: 5239 Cov.: 31 AF XY: 0.249 AC XY: 18471 AN XY: 74294

African (AFR) AF: 0.385 AC: 15966 AN: 41474

American (AMR) AF: 0.192 AC: 2928 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3466

East Asian (EAS) AF: 0.315 AC: 1624 AN: 5160

South Asian (SAS) AF: 0.209 AC: 1006 AN: 4812

European-Finnish (FIN) AF: 0.307 AC: 3238 AN: 10550

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11077 AN: 67966

Other (OTH) AF: 0.222 AC: 469 AN: 2108

Alfa AF: 0.204 Hom.: 441

Bravo AF: 0.243

Asia WGS AF: 0.288 AC: 999 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		0.63
PromoterAI		-0.031	Neutral
Mutation Taster		=87/13	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17036526; hg19: chr2-47572363;