rs1555515437
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_004360.5(CDH1):c.739G>A(p.Glu247Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
CDH1
NM_004360.5 missense
NM_004360.5 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 7.66
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a domain Cadherin 1 (size 107) in uniprot entity CADH1_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_004360.5
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.739G>A | p.Glu247Lys | missense_variant | 6/16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.739G>A | p.Glu247Lys | missense_variant | 6/15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-877G>A | 5_prime_UTR_variant | 6/16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1081G>A | 5_prime_UTR_variant | 6/15 | NP_001304115.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 27, 2018 | The p.E247K variant (also known as c.739G>A), located in coding exon 6 of the CDH1 gene, results from a G to A substitution at nucleotide position 739. The glutamic acid at codon 247 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | This missense variant replaces glutamic acid with lysine at codon 247 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;D
REVEL
Benign
Sift
Uncertain
D;.;.;.;D
Sift4G
Uncertain
T;T;D;T;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of ubiquitination at E247 (P = 0.0219);Gain of ubiquitination at E247 (P = 0.0219);Gain of ubiquitination at E247 (P = 0.0219);Gain of ubiquitination at E247 (P = 0.0219);Gain of ubiquitination at E247 (P = 0.0219);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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