10-71807740-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_022124.6(CDH23):c.8533C>T(p.Arg2845Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,606,860 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. R2845H) 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.8533C>T | p.Arg2845Cys | missense_variant | 59/70 | ENST00000224721.12 | |
CDH23 | NM_001171933.1 | c.1813C>T | p.Arg605Cys | missense_variant | 12/23 | ||
CDH23 | NM_001171934.1 | c.1813C>T | p.Arg605Cys | missense_variant | 12/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.8533C>T | p.Arg2845Cys | missense_variant | 59/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000424 AC: 10AN: 235858Hom.: 0 AF XY: 0.0000391 AC XY: 5AN XY: 127906
GnomAD4 exome AF: 0.0000275 AC: 40AN: 1454654Hom.: 0 Cov.: 32 AF XY: 0.0000194 AC XY: 14AN XY: 723002
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 26, 2017 | The p.Arg2845Cys variant (rs727505254) has not been reported in the medical literature, nor has it been previously identified in our laboratory. The p.Arg2845Cys variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.005% (identified in 13 out of 263,592 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 179973). The arginine at codon 2845 is highly conserved considering 12 species up to zebrafish (Alamut software v2.10.0), and computational analyses suggest that this variant affects the structure/function of the CDH23 protein (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Arg2845Cys variant cannot be determined with certainty. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 05, 2018 | The R2845C variant in the CDH23 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R2845C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 07, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2845 of the CDH23 protein (p.Arg2845Cys). This variant is present in population databases (rs727505254, gnomAD 0.01%). 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: 179973). 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 | Sep 09, 2014 | The Arg2845Cys variant in CDH23 has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analyses do not provide strong support for or against an impa ct to the protein. In summary, the clinical significance of the Arg2845Cys varia nt is uncertain. - |
CDH23-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2024 | The c.8533C>T (p.R2845C) alteration is located in exon 59 (coding exon 58) of the CDH23 gene. This alteration results from a C to T substitution at nucleotide position 8533, causing the arginine (R) at amino acid position 2845 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at