rs569086883
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting
The NM_004360.5(CDH1):c.2072C>A(p.Ala691Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. A691T) has been classified as Likely benign.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2072C>A | p.Ala691Asp | missense_variant | 13/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1889C>A | p.Ala630Asp | missense_variant | 12/15 | ||
CDH1 | NM_001317185.2 | c.524C>A | p.Ala175Asp | missense_variant | 13/16 | ||
CDH1 | NM_001317186.2 | c.107C>A | p.Ala36Asp | missense_variant | 12/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2072C>A | p.Ala691Asp | missense_variant | 13/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | upstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152050Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251420Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135884
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461798Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727202
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152168Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | This missense variant replaces alanine with aspartic acid at codon 691 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 been identified in 1/251420 chromosomes 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2023 | The p.A691D variant (also known as c.2072C>A), located in coding exon 13 of the CDH1 gene, results from a C to A substitution at nucleotide position 2072. The alanine at codon 691 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is not 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2017 | This variant is denoted CDH1 c.2072C>A at the cDNA level, p.Ala691Asp (A691D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Ala691Asp was not observed at a significant allele frequency in 1000 Genomes. Since Alanine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Ala691Asp occurs at a position that is not conserved and is located in the Cadherin 5 domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether CDH1 Ala691Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 691 of the CDH1 protein (p.Ala691Asp). This variant is present in population databases (rs569086883, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449851). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at