2-47369579-A-T

Position:

• chr2-47369579-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_002354.3(EPCAM):​c.74A>T​(p.Glu25Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/27 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EPCAM NM_002354.3 missense, splice_region
• Scores: Splicing: ADA: 0.01880
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.848

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 2 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=0.07751259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPCAM	NM_002354.3	c.74A>T	p.Glu25Val	missense_variant, splice_region_variant	1/9	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9	c.74A>T	p.Glu25Val	missense_variant, splice_region_variant	1/9	1	NM_002354.3	ENSP00000263735	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438344 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713408

Gnomad4 AFR exome AF: 0.00

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2016

This sequence change replaces glutamic acid with valine at codon 25 of the EPCAM protein (p.Glu25Val). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a EPCAM-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a novel missense change with uncertain impact on splicing and protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Benign	0.78
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.11	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.063
Sift	Benign	0.24	T;D
Sift4G	Benign	0.28	T;D
Polyphen		0.010	B;.
Vest4		0.19
MutPred		0.25		Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);
MVP		0.35
MPC		0.013
ClinPred		0.12	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.29
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.019
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: -2
DS_DL_spliceai		0.92		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854494; hg19: chr2-47596718;