rs58450758

chr2-47377727-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002354.3(EPCAM):c.555+650C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 433,168 control chromosomes in the GnomAD database, including 4,793 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 0.17 (2925 hom., cov: 30)
  • Exomes 𝑓: 0.10 (1868 hom.)
• Consequence: EPCAM NM_002354.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.641

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]

MIR559 (HGNC:32815): (microRNA 559) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3	c.555+650C>T		intron_variant		ENST00000263735.9
MIR559	NR_030286.1	n.53C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPCAM	ENST00000263735.9	c.555+650C>T		intron_variant		1	NM_002354.3	P1
MIR559	ENST00000385188.1	n.53C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 24999 AN: 151066 Hom.: 2913 Cov.: 30

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.0639

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0694

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0820

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.122 AC: 14566 AN: 119442 Hom.: 1182 AF XY: 0.116 AC XY: 7376 AN XY: 63680

Gnomad AFR exome AF: 0.337

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.0609

Gnomad EAS exome AF: 0.191

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.0808

Gnomad OTH exome AF: 0.0980

GnomAD4 exome AF: 0.105 AC: 29535 AN: 281982 Hom.: 1868 Cov.: 0 AF XY: 0.104 AC XY: 16744 AN XY: 161754

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.0592

Gnomad4 EAS exome AF: 0.188

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.0831

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.166 AC: 25035 AN: 151186 Hom.: 2925 Cov.: 30 AF XY: 0.168 AC XY: 12401 AN XY: 73800

Gnomad4 AFR AF: 0.330

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0694

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.0820

Gnomad4 OTH AF: 0.143

Alfa AF: 0.110 Hom.: 725

Bravo AF: 0.172

Asia WGS AF: 0.187 AC: 650 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	3.6
Dann	Benign	0.17

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs58450758; hg19: chr2-47604866; COSMIC: COSV55394564; COSMIC: COSV55394564;