2-47345224-G-C

Position:

• chr2-47345224-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The ENST00000405271.5(EPCAM):​c.-149+1G>C variant causes a splice donor 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.634

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06316812 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPCAM	ENST00000405271.5	c.-149+1G>C		splice_donor_variant		5
EPCAM	ENST00000456133.5	c.-149+1G>C		splice_donor_variant, NMD_transcript_variant		5

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

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.222

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17036526; hg19: chr2-47572363;