rs397517353
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_022124.6(CDH23):c.7776G>A(p.Trp2592Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,442,194 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_022124.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.7776G>A | p.Trp2592Ter | stop_gained | 55/70 | ENST00000224721.12 | |
CDH23 | NM_001171933.1 | c.1056G>A | p.Trp352Ter | stop_gained | 8/23 | ||
CDH23 | NM_001171934.1 | c.1056G>A | p.Trp352Ter | stop_gained | 8/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.7776G>A | p.Trp2592Ter | stop_gained | 55/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.0000140 AC: 3AN: 214472Hom.: 0 AF XY: 0.00000861 AC XY: 1AN XY: 116086
GnomAD4 exome AF: 0.00000277 AC: 4AN: 1442194Hom.: 0 Cov.: 34 AF XY: 0.00000140 AC XY: 1AN XY: 715588
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 11, 2023 | ClinVar contains an entry for this variant (Variation ID: 46039). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CDH23-related conditions. This sequence change creates a premature translational stop signal (p.Trp2592*) in the CDH23 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH23 are known to be pathogenic (PMID: 11138009, 21940737). This variant is present in population databases (rs397517353, gnomAD 0.007%). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 03, 2012 | The Trp2592X variant in CDH23 has not been reported in the literature nor previo usly identified by our laboratory. However, the Trp2592X variant leads to a prem ature stop codon at position 2592, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at