rs199668532
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_022124.6(CDH23):c.8534G>A(p.Arg2845His) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,606,246 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2845C) has been classified as Uncertain significance.
Frequency
Consequence
NM_022124.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.8534G>A | p.Arg2845His | missense_variant | 59/70 | ENST00000224721.12 | |
CDH23 | NM_001171933.1 | c.1814G>A | p.Arg605His | missense_variant | 12/23 | ||
CDH23 | NM_001171934.1 | c.1814G>A | p.Arg605His | missense_variant | 12/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.8534G>A | p.Arg2845His | missense_variant | 59/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000341 AC: 8AN: 234582Hom.: 0 AF XY: 0.0000236 AC XY: 3AN XY: 127216
GnomAD4 exome AF: 0.000115 AC: 167AN: 1454038Hom.: 0 Cov.: 32 AF XY: 0.000116 AC XY: 84AN XY: 722626
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | CDH23: PM2, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2845 of the CDH23 protein (p.Arg2845His). This variant is present in population databases (rs199668532, gnomAD 0.005%). 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: 179385). 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 C0"). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 22, 2013 | The Arg2845His variant in CDH23 has not been previously reported in individuals with hearing loss but has been reported in 1/1152 (0.2%) chromosomes from a broa d population by the CLINSEQ project (dbSNP rs199668532). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT ) do not provide strong support for or against an impact to the protein. In summ ary, additional data is needed to determine the clinical significance of this va riant. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 21, 2024 | The c.8534G>A (p.R2845H) alteration is located in exon 59 (coding exon 58) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 8534, causing the arginine (R) at amino acid position 2845 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
Hearing impairment Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PM2_Moderate, PP3_Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at