rs397517308
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_022124.6(CDH23):c.1478G>A(p.Gly493Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G493G) has been classified as Likely benign.
Frequency
Consequence
NM_022124.6 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1478G>A | p.Gly493Glu | missense_variant | 15/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.1478G>A | p.Gly493Glu | missense_variant | 15/32 | ||
CDH23 | NM_001171931.2 | c.1478G>A | p.Gly493Glu | missense_variant | 15/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1478G>A | p.Gly493Glu | missense_variant | 15/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249234Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135222
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461672Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727110
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 28, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Gly493Glu v ariant in CDH23 has not been reported nor previously identified by our laborator y. This variant has not been identified in large and broad European American an d African American populations by the NHLBI Exome Sequencing Project (http://evs .gs.washington.edu/EVS). Computational analyses (biochemical amino acid properti es, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly493Glu var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 02, 2022 | Variant summary: CDH23 c.1478G>A (p.Gly493Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249234 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1478G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 04, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 493 of the CDH23 protein (p.Gly493Glu). This variant is present in population databases (rs397517308, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 45874). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). 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