rs183431253
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_022124.6(CDH23):c.6049G>A(p.Gly2017Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G2017G) has been classified as Likely benign.
Frequency
Consequence
NM_022124.6 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.6049G>A | p.Gly2017Ser | missense_variant, splice_region_variant | 46/70 | ENST00000224721.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.6049G>A | p.Gly2017Ser | missense_variant, splice_region_variant | 46/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000287 AC: 7AN: 243642Hom.: 0 AF XY: 0.0000301 AC XY: 4AN XY: 132708
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1459876Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726252
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74456
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 28, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2017 of the CDH23 protein (p.Gly2017Ser). This variant also falls at the last nucleotide of exon 46, which is part of the consensus splice site for this exon. This variant is present in population databases (rs183431253, gnomAD 0.02%). This missense change has been observed in individuals with Usher syndrome (PMID: 18323324, 23451239, 25404053). ClinVar contains an entry for this variant (Variation ID: 46000). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Studies have shown that this missense change alters CDH23 gene expression (PMID: 23451239). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2021 | Published functional studies demonstrate a damaging splicing effect with skipping of exon 46 likely resulting in nonsense-mediated decay (Aparisi et al., 2013); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32488467, 23451239, 16679490, 27535533, 18429043, 25404053, 18323324, 25525159) - |
Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pituitary adenoma 5, multiple types Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 25, 2023 | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 23, 2011 | The Gly2017Ser variant in CDH23 has been reported in 2 probands with Usher synd rome type I and was absent from 192 control chromosomes (Oshima 2008, Roux 2006) . One of these probands was homozygous and the other was compound heterozygous w ith another pathogenic CDH23 variant. The Gly2017Ser variant occurs in the last base of the exon. This position has been shown to be part of the splicing consen sus sequence and splicing prediction models predict that this variant could affe ct splicing. In summary, this variant is likely to be pathogenic. - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, flagged submission | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The CDH23 c.6049G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at