rs200263980
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_022124.6(CDH23):c.1745G>A(p.Arg582Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00005 in 1,558,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R582W) has been classified as Uncertain significance.
Frequency
Consequence
NM_022124.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1745G>A | p.Arg582Gln | missense_variant | 16/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.1745G>A | p.Arg582Gln | missense_variant | 16/32 | ||
CDH23 | NM_001171931.2 | c.1745G>A | p.Arg582Gln | missense_variant | 16/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1745G>A | p.Arg582Gln | missense_variant | 16/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000303 AC: 5AN: 165250Hom.: 0 AF XY: 0.0000228 AC XY: 2AN XY: 87756
GnomAD4 exome AF: 0.0000505 AC: 71AN: 1406454Hom.: 0 Cov.: 31 AF XY: 0.0000590 AC XY: 41AN XY: 694486
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74340
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 | Jul 23, 2013 | The Arg582Gln variant in CDH23 has been reported in 1 Dutch individual with nons yndromic hearing loss; however, a second CDH23 variant was not identified in thi s individual (Astuto 2002). This variant has been identified in 0.02% (2/8324) o f European American chromosomes by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS/; dbSNP rs200263980). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agai nst an impact to the protein. In summary, additional information is needed to fu lly assess the clinical significance of the Arg582Gln variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2021 | Variant summary: CDH23 c.1745G>A (p.Arg582Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 165250 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1745G>A has been reported in the literature in at least one individual affected with recessive nonsyndromic deafness (Astuto_2002). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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. | Jan 19, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 582 of the CDH23 protein (p.Arg582Gln). This variant is present in population databases (rs200263980, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of CDH23-related conditions (PMID: 12075507). ClinVar contains an entry for this variant (Variation ID: 177725). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDH23 protein function. 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