dbSNP rs772471530: EPCAM:p.Pro178Arg (chr2-47377055-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002354.3(EPCAM):c.533C>G(p.Pro178Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P178A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.97

Publications

2 publications found

Variant links:

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]

EPCAM Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 8
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital diarrhea 5 with tufting enteropathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EPCAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.108897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.533C>G	p.Pro178Arg	missense_variant	Exon 5 of 9	ENST00000263735.9	NP_002345.2	P16422

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPCAM	ENST00000263735.9 link	c.533C>G	p.Pro178Arg	missense_variant	Exon 5 of 9	1	NM_002354.3	ENSP00000263735.4	P16422
EPCAM	ENST00000405271.5 link	c.617C>G	p.Pro206Arg	missense_variant	Exon 6 of 10	5		ENSP00000385476.1	B5MCA4
EPCAM	ENST00000456133.5 link	n.617C>G		non_coding_transcript_exon_variant	Exon 6 of 11	5		ENSP00000410675.1	B5MCA4
EPCAM	ENST00000490733.1 link	n.382C>G		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P178R variant (also known as c.533C>G), located in coding exon 5 of the EPCAM gene, results from a C to G substitution at nucleotide position 533. The proline at codon 178 is replaced by arginine, an amino acid with dissimilar 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

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

3.1

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.029

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.52

.;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.6

.;L

PhyloP100

-2.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.064

Sift

Benign

0.11

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0030

B;B

Vest4

0.20

MutPred

0.46

Gain of loop (P = 0.0111);.;

MVP

0.39

MPC

0.013

ClinPred

0.071

GERP RS

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.079

gMVP

0.29

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over