NM_002354.3:c.74A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 16/28 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E25D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EPCAM
NM_002354.3 missense, splice_region

Scores

1
18
Splicing: ADA: 0.01880
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.848

Publications

1 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

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=0.07751259).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EPCAMNM_002354.3 linkc.74A>T p.Glu25Val missense_variant, splice_region_variant Exon 1 of 9 ENST00000263735.9 NP_002345.2 P16422

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EPCAMENST00000263735.9 linkc.74A>T p.Glu25Val missense_variant, splice_region_variant Exon 1 of 9 1 NM_002354.3 ENSP00000263735.4 P16422

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
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32874
American (AMR)
AF:
0.00
AC:
0
AN:
40600
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25488
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38758
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82428
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5136
European-Non Finnish (NFE)
AF:
0.00000181
AC:
2
AN:
1102934
Other (OTH)
AF:
0.00
AC:
0
AN:
59508
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jan 05, 2016
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 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 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;.
PhyloP100
0.85
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
PromoterAI
0.094
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.29
gMVP
0.54
Mutation Taster
=95/5
polymorphism

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

Other links and lift over

dbSNP: rs878854494; hg19: chr2-47596718; API