rs786204192

Variant names:

• chr2-47385185-G-A
• rs786204192
• NM_002354.3:c.878G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47385185-G-A
• chr2-47385185-G-C
• chr2-47385185-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_002354.3(EPCAM):​c.878G>A​(p.Arg293Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EPCAM NM_002354.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.882

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a chain Epithelial cell adhesion molecule (size 290) in uniprot entity EPCAM_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_002354.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04033938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3	c.878G>A	p.Arg293Lys	missense_variant	Exon 8 of 9	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9	c.878G>A	p.Arg293Lys	missense_variant	Exon 8 of 9	1	NM_002354.3	ENSP00000263735.4
EPCAM	ENST00000405271.5	c.962G>A	p.Arg321Lys	missense_variant	Exon 9 of 10	5		ENSP00000385476.1
EPCAM	ENST00000456133.5	n.962G>A		non_coding_transcript_exon_variant	Exon 9 of 11	5		ENSP00000410675.1
EPCAM	ENST00000490733.1	n.727G>A		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460900 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726840

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Dec 04, 2014

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine with lysine at codon 293 of the EPCAM protein ((p.Arg293Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This sequence change has not been published in the literature and is not present in population databases. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be tolerated, but these predictions have not been confirmed by published functional studies. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R293K variant (also known as c.878G>A), located in coding exon 8 of the EPCAM gene, results from a G to A substitution at nucleotide position 878. The arginine at codon 293 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.53
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.56	.;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.038
Sift	Benign	0.67	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0050	B;B
Vest4		0.11
MutPred		0.29		Gain of methylation at R321 (P = 0.0224);.;
MVP		0.34
MPC		0.013
ClinPred		0.059	T
GERP RS		0.72
Varity_R		0.032
gMVP		0.15

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: rs786204192; hg19: chr2-47612324;