2-47385185-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002354.3(EPCAM):c.878G>T(p.Arg293Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R293K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.882

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18889046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.878G>T	p.Arg293Ile	missense_variant	Exon 8 of 9	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EPCAM	ENST00000263735.9 link	c.878G>T	p.Arg293Ile	missense_variant	Exon 8 of 9	1	NM_002354.3	ENSP00000263735.4
EPCAM	ENST00000405271.5 link	c.962G>T	p.Arg321Ile	missense_variant	Exon 9 of 10	5		ENSP00000385476.1
EPCAM	ENST00000456133.5 link	n.962G>T		non_coding_transcript_exon_variant	Exon 9 of 11	5		ENSP00000410675.1
EPCAM	ENST00000490733.1 link	n.727G>T		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460900

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111278

Other (OTH)

AF:

0.0000166

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Apr 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R293I variant (also known as c.878G>T), located in coding exon 8 of the EPCAM gene, results from a G to T substitution at nucleotide position 878. The arginine at codon 293 is replaced by isoleucine, an amino acid with 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

0.29

BayesDel_addAF

Benign

0.0041

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.30

T;D

Eigen

Benign

0.0036

Eigen_PC

Benign

-0.080

FATHMM_MKL

Benign

0.42

LIST_S2

Uncertain

0.87

.;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.6

.;M

PhyloP100

0.88

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

0.97

D;P

Vest4

0.31

MutPred

0.34

Loss of disorder (P = 0.0219);.;

MVP

0.79

MPC

0.053

ClinPred

0.98

GERP RS

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.22

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over