chr2-47379778-G-C
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_002354.3(EPCAM):c.667G>C(p.Glu223Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,612,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. E223K) has been classified as Uncertain significance.
Frequency
Consequence
NM_002354.3 missense
Scores
Clinical Significance
Conservation
Publications
- Lynch syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Lynch syndrome 8Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- congenital diarrhea 5 with tufting enteropathyInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EPCAM | ENST00000263735.9 | c.667G>C | p.Glu223Gln | missense_variant | Exon 7 of 9 | 1 | NM_002354.3 | ENSP00000263735.4 | ||
EPCAM | ENST00000405271.5 | c.751G>C | p.Glu251Gln | missense_variant | Exon 8 of 10 | 5 | ENSP00000385476.1 | |||
EPCAM | ENST00000456133.5 | n.751G>C | non_coding_transcript_exon_variant | Exon 8 of 11 | 5 | ENSP00000410675.1 | ||||
EPCAM | ENST00000490733.1 | n.516G>C | non_coding_transcript_exon_variant | Exon 5 of 6 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251346 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460844Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6AN XY: 726778 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 223 of the EPCAM protein (p.Glu223Gln). This variant is present in population databases (rs372674836, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with EPCAM-related conditions. ClinVar contains an entry for this variant (Variation ID: 216560). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.E223Q variant (also known as c.667G>C), located in coding exon 7 of the EPCAM gene, results from a G to C substitution at nucleotide position 667. The glutamic acid at codon 223 is replaced by glutamine, an amino acid with highly 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at