rs863224725
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004360.5(CDH1):c.1565C>A(p.Thr522Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 16/22 in silico tools predict a benign outcome for this variant. 2/2 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. T522I) has been classified as Benign.
Frequency
Consequence
NM_004360.5 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1565C>A | p.Thr522Lys | missense_variant, splice_region_variant | 10/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1382C>A | p.Thr461Lys | missense_variant, splice_region_variant | 9/15 | ||
CDH1 | NM_001317185.2 | c.17C>A | p.Thr6Lys | missense_variant, splice_region_variant | 10/16 | ||
CDH1 | NM_001317186.2 | c.-255C>A | splice_region_variant, 5_prime_UTR_variant | 10/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1565C>A | p.Thr522Lys | missense_variant, splice_region_variant | 10/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.264-100G>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251328Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135850
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2021 | This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 522 of the CDH1 protein (p.Thr522Lys). 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. 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. ClinVar contains an entry for this variant (Variation ID: 483244). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 22, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2022 | The p.T522K variant (also known as c.1565C>A), located in coding exon 10 of the CDH1 gene, results from a C to A substitution at nucleotide position 1565. The threonine at codon 522 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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