rs727504455
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_022124.6(CDH23):c.1369C>T(p.Arg457Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 4.00
Genes affected
CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1369C>T | p.Arg457Trp | missense_variant | 14/70 | ENST00000224721.12 | NP_071407.4 | |
CDH23 | NM_001171930.2 | c.1369C>T | p.Arg457Trp | missense_variant | 14/32 | NP_001165401.1 | ||
CDH23 | NM_001171931.2 | c.1369C>T | p.Arg457Trp | missense_variant | 14/26 | NP_001165402.1 | ||
CDH23 | NM_052836.4 | c.1369C>T | p.Arg457Trp | missense_variant | 14/14 | NP_443068.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1369C>T | p.Arg457Trp | missense_variant | 14/70 | 5 | NM_022124.6 | ENSP00000224721 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249304Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135246
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727138
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 08, 2023 | 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. ClinVar contains an entry for this variant (Variation ID: 178675). This missense change has been observed in individual(s) with Usher syndrome (PMID: 22135276; Invitae). This variant is present in population databases (rs727504455, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 457 of the CDH23 protein (p.Arg457Trp). - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 01, 2013 | The Arg457Trp variant in CDH23 has been reported in 1/188 individuals with Usher syndrome and 2/878 control chromosomes (Le Quesne Stabej 2012). Although this variant has been seen in controls, its frequency is low enough to be consistent with a recessive carrier frequency. In addition, Computational analyses (biochem ical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sugges t that the Arg457Trp variant may impact the protein, though this information alo ne is not predictive enough to determine pathogenicity. Furthermore, the identif ication of this variant in trans with a pathogenic CDH23 variant in two affected children in this family increases the likelihood that this variant is pathogeni c. In summary, based on the identification of this variant in two affected famil y members with a second pathogenic CDH23 variant, this variant is likely to be p athogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;D;.;.;.;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;.;M;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;.;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
D;D;.;D;D;D;D;.;.
Polyphen
1.0, 1.0
.;.;D;D;.;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0437);Loss of disorder (P = 0.0437);Loss of disorder (P = 0.0437);Loss of disorder (P = 0.0437);Loss of disorder (P = 0.0437);.;Loss of disorder (P = 0.0437);Loss of disorder (P = 0.0437);.;
MVP
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at