chr2-47377727-C-T

Variant names:

• chr2-47377727-C-T
• rs58450758
• NM_002354.3:c.555+650C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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]

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
EPCAM	NM_002354.3	c.555+650C>T		intron_variant	Intron 5 of 8	ENST00000263735.9	NP_002345.2
MIR559	NR_030286.1	n.53C>T		non_coding_transcript_exon_variant	Exon 1 of 1
MIR559	unassigned_transcript_347	n.*17C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9	c.555+650C>T		intron_variant	Intron 5 of 8	1	NM_002354.3	ENSP00000263735.4

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

GnomAD2 exomes AF: 0.122 AC: 14566 AN: 119442 AF XY: 0.116

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 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

African (AFR) AF: 0.323 AC: 1863 AN: 5772

American (AMR) AF: 0.139 AC: 2387 AN: 17148

Ashkenazi Jewish (ASJ) AF: 0.0592 AC: 539 AN: 9108

East Asian (EAS) AF: 0.188 AC: 1325 AN: 7064

South Asian (SAS) AF: 0.106 AC: 5655 AN: 53560

European-Finnish (FIN) AF: 0.148 AC: 4049 AN: 27338

Middle Eastern (MID) AF: 0.0662 AC: 76 AN: 1148

European-Non Finnish (NFE) AF: 0.0831 AC: 12329 AN: 148302

Other (OTH) AF: 0.105 AC: 1312 AN: 12542

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

African (AFR) AF: 0.330 AC: 13588 AN: 41216

American (AMR) AF: 0.137 AC: 2085 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.0694 AC: 240 AN: 3456

East Asian (EAS) AF: 0.194 AC: 970 AN: 4996

South Asian (SAS) AF: 0.127 AC: 600 AN: 4726

European-Finnish (FIN) AF: 0.153 AC: 1602 AN: 10482

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0820 AC: 5558 AN: 67788

Other (OTH) AF: 0.143 AC: 302 AN: 2108

Alfa AF: 0.146 Hom.: 1845

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
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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