rs878854488
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_002354.3(EPCAM):c.429G>A(p.Trp143Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000344 in 1,453,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
EPCAM
NM_002354.3 stop_gained
NM_002354.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 6.16
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-47375237-G-A is Pathogenic according to our data. Variant chr2-47375237-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 239127.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPCAM | NM_002354.3 | c.429G>A | p.Trp143Ter | stop_gained | 4/9 | ENST00000263735.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPCAM | ENST00000263735.9 | c.429G>A | p.Trp143Ter | stop_gained | 4/9 | 1 | NM_002354.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251230Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135810
GnomAD3 exomes
AF:
AC:
2
AN:
251230
Hom.:
AF XY:
AC XY:
2
AN XY:
135810
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1453182Hom.: 0 Cov.: 29 AF XY: 0.00000553 AC XY: 4AN XY: 723494
GnomAD4 exome
AF:
AC:
5
AN:
1453182
Hom.:
Cov.:
29
AF XY:
AC XY:
4
AN XY:
723494
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2015 | This sequence change creates a premature translational stop signal at codon 143 (p.Trp143*). It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in EPCAM are known to be pathogenic (PMID: 24142340). Exon level deletions at the 3' end of EPCAM, involving exon 9 minimally, lead to transcriptional read-through into the neighboring MSH2 gene, triggering epigenetic silencing and inactivation of MSH2 (PMID: 19098912, 23938213). Loss of MSH2 subsequently causes Lynch syndrome (PMID: 23264089, 19455606, 15849733). Other pathogenic sequence changes, such as this variant c.429G>A p.Trp143*, which disrupt EPCAM protein function alone, are known causes of autosomal recessive congenital tufting enteropathy (PMID: 18572020, 20034091, 23462293). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at