rs748047907
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_022124.6(CDH23):c.2870G>A(p.Arg957His) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,612,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict 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. R957C) 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.2870G>A | p.Arg957His | missense_variant | 25/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.2870G>A | p.Arg957His | missense_variant | 25/32 | ||
CDH23 | NM_001171931.2 | c.2870G>A | p.Arg957His | missense_variant | 25/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.2870G>A | p.Arg957His | missense_variant | 25/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000366 AC: 9AN: 246052Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134526
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1460340Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 726498
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 09, 2016 | The p.Arg957His variant in CDH23 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 3/63566 Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs748047907). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Comp utational prediction tools and conservation analyses do not provide strong suppo rt for or against an impact to the protein. In summary, the clinical significanc e of the p.Arg957His variant is uncertain. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 957 of the CDH23 protein (p.Arg957His). This variant is present in population databases (rs748047907, gnomAD 0.006%). 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: 505137). 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 C25"). 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