Genetic Variant NM_002354.3:c.878G>C (chr2-47385185-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002354.3(EPCAM):c.878G>C(p.Arg293Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.882

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 links:

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ACMG classification

Classification made for transcript

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=0.12948886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.878G>C	p.Arg293Thr	missense_variant	Exon 8 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.878G>C	p.Arg293Thr	missense_variant	Exon 8 of 9	1	NM_002354.3	ENSP00000263735.4	P16422
EPCAM	ENST00000405271.5 link	c.962G>C	p.Arg321Thr	missense_variant	Exon 9 of 10	5		ENSP00000385476.1	B5MCA4
EPCAM	ENST00000456133.5 link	n.962G>C		non_coding_transcript_exon_variant	Exon 9 of 11	5		ENSP00000410675.1	B5MCA4
EPCAM	ENST00000490733.1 link	n.727G>C		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.30

T;D

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.083

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.031

D;D

Polyphen

0.67

P;P

Vest4

0.27

MutPred

0.28

Loss of MoRF binding (P = 0.0422);.;

MVP

0.77

MPC

0.024

ClinPred

0.77

GERP RS

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over