rs199508694
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_022124.6(CDH23):c.1637G>A(p.Arg546Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000733 in 1,610,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R546L) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1637G>A | p.Arg546Gln | missense_variant | 16/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.1637G>A | p.Arg546Gln | missense_variant | 16/32 | ||
CDH23 | NM_001171931.2 | c.1637G>A | p.Arg546Gln | missense_variant | 16/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1637G>A | p.Arg546Gln | missense_variant | 16/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000243 AC: 37AN: 152130Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000870 AC: 21AN: 241258Hom.: 1 AF XY: 0.0000687 AC XY: 9AN XY: 130950
GnomAD4 exome AF: 0.0000556 AC: 81AN: 1457920Hom.: 0 Cov.: 31 AF XY: 0.0000552 AC XY: 40AN XY: 724736
GnomAD4 genome ? AF: 0.000243 AC: 37AN: 152248Hom.: 1 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 30, 2012 | The Arg546Gln variant in CDH23 has not been reported in the literature, but has now been identified in 2/36 Black or African American individuals with hearing l oss by our laboratory, neither of whom has a second CDH23 variant. In addition, this variant has been identified in 0.1% (4/4234) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS/). However, this frequency is not enough to rule out a pathoge nic role. Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional data is needed to determine the clinical significance of this variant. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 17, 2023 | The c.1637G>A (p.R546Q) alteration is located in exon 16 (coding exon 15) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 1637, causing the arginine (R) at amino acid position 546 to be replaced by a glutamine (Q). 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. | Oct 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at