rs115212523

chr2-47373968-G-Achr2-47373968-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002354.3(EPCAM):c.345G>A(p.Met115Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,614,116 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M115T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: EPCAM NM_002354.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.191

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010049552).
• BP6: Variant 2-47373968-G-A is Benign according to our data. Variant chr2-47373968-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560809.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00291 (443/152234) while in subpopulation AFR AF= 0.00924 (384/41546). AF 95% confidence interval is 0.00848. There are 2 homozygotes in gnomad4. There are 215 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3	c.345G>A	p.Met115Ile	missense_variant	3/9	ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPCAM	ENST00000263735.9	c.345G>A	p.Met115Ile	missense_variant	3/9	1	NM_002354.3	P1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 442 AN: 152116 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00925

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000895 AC: 225 AN: 251466 Hom.: 1 AF XY: 0.000765 AC XY: 104 AN XY: 135912

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000330 AC: 483 AN: 1461882 Hom.: 3 Cov.: 33 AF XY: 0.000293 AC XY: 213 AN XY: 727246

Gnomad4 AFR exome AF: 0.00777

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00291 AC: 443 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00289 AC XY: 215 AN XY: 74426

Gnomad4 AFR AF: 0.00924

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000461 Hom.: 0

Bravo AF: 0.00354

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00101 AC: 123

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2023

The p.M115I variant (also known as c.345G>A), located in coding exon 3 of the EPCAM gene, results from a G to A substitution at nucleotide position 345. The methionine at codon 115 is replaced by isoleucine, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Benign	0.84
DEOGEN2	Benign	0.011	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.17
MutPred		0.59		Gain of sheet (P = 0.0043);.;.;
MVP		0.40
MPC		0.013
ClinPred		0.0016	T
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs115212523; hg19: chr2-47601107;