rs786202785
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3PP5_Moderate
The NM_004360.5(CDH1):c.2272G>A(p.Glu758Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E758G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2272G>A | p.Glu758Lys | missense_variant | 14/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2089G>A | p.Glu697Lys | missense_variant | 13/15 | ||
CDH1 | NM_001317185.2 | c.724G>A | p.Glu242Lys | missense_variant | 14/16 | ||
CDH1 | NM_001317186.2 | c.307G>A | p.Glu103Lys | missense_variant | 13/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2272G>A | p.Glu758Lys | missense_variant | 14/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 08, 2014 | The p.E758K variant (also known as c.2272G>A), located in coding exon 14 of the CDH1 gene, results from a G to A substitution at nucleotide position 2272. The glutamic acid at codon 758 is replaced by lysine, an amino acid with dissimilar properties. This variant is located in the CDH1 juxtamembrane domain responsible for clustering of cadherins in the cell membrane and for cellular adhesive strength via p120-catenin and was detected by our laboratory in a family with clinical history consistent with Hereditary Diffuse Gastric Cancer. Structurally, the position E758 is important for its negative charge and its location in the p120 interaction motif. Mutating this position from a negative charge to a positive charge would act to repel this interaction (Ishiyama N, et al. Cell 2010 Apr; 141(1):117-28). This can be seen with the studies on the adjacent position E757K (Figueiredo J, et al. Eur. J. Hum. Genet. 2013 Mar; 21(3):301-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 45000 alleles tested) in our clinical cohort (includes this individual). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by, PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at