16-68808838-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_004360.5(CDH1):c.677C>T(p.Ala226Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.677C>T | p.Ala226Val | missense_variant | Exon 5 of 16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.677C>T | p.Ala226Val | missense_variant | Exon 5 of 15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-939C>T | 5_prime_UTR_variant | Exon 5 of 16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1143C>T | 5_prime_UTR_variant | Exon 5 of 15 | NP_001304115.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461660Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727124
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:3
The CDH1 p.Ala226Val variant was not identified in the literature nor was it identified in the dbSNP database. The variant was identified in ClinVar (classified as uncertain significance by Invitae). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Ala226 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 226 of the CDH1 protein (p.Ala226Val). This variant is not present in population databases (gnomAD no frequency). 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: 463789). 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. -
PM2 (PMID: 30311375) -
Hereditary cancer-predisposing syndrome Uncertain:2
The p.A226V variant (also known as c.677C>T), located in coding exon 5 of the CDH1 gene, results from a C to T substitution at nucleotide position 677. The alanine at codon 226 is replaced by valine, an amino acid with similar 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. -
This missense variant replaces alanine with valine at codon 226 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at