rs772995621
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_022124.6(CDH23):c.499G>A(p.Val167Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,746 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 (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 7.60
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 Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.24604192).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.499G>A | p.Val167Ile | missense_variant | 7/70 | ENST00000224721.12 | NP_071407.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.499G>A | p.Val167Ile | missense_variant | 7/70 | 5 | NM_022124.6 | ENSP00000224721 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248922Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135052
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461536Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727016
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 15, 2017 | The p.Val167Ile variant in CDH23 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 4/126512 Europe an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs772995621). Although this variant has been seen in the gene ral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong s upport for or against an impact to the protein. In summary, the clinical signifi cance of the p.Val167Ile variant is uncertain. ACMG/AMP Criteria applied: PM2. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2022 | The c.499G>A (p.V167I) alteration is located in exon 7 (coding exon 6) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 499, causing the valine (V) at amino acid position 167 to be replaced by an isoleucine (I). 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. | Apr 11, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 20, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 167 of the CDH23 protein (p.Val167Ile). This variant is present in population databases (rs772995621, 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: 517628). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.;.;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;N;N;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;.;.;.;.
REVEL
Benign
Sift
Benign
T;.;.;.;.;.;.;.;.
Sift4G
Benign
T;D;.;T;T;T;D;.;.
Polyphen
0.77, 1.0
.;.;P;D;.;.;.;.;.
Vest4
MVP
ClinPred
D
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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