chr10-71803371-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_022124.6(CDH23):c.7823G>A(p.Arg2608His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,600,450 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).
Frequency
Genomes: 𝑓 0.00057 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00070 ( 1 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
4
5
10
Clinical Significance
Conservation
PhyloP100: 7.78
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 -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.1011363).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000572 (87/152094) while in subpopulation AMR AF= 0.00144 (22/15282). AF 95% confidence interval is 0.000975. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDH23 | NM_022124.6 | c.7823G>A | p.Arg2608His | missense_variant | 55/70 | ENST00000224721.12 | NP_071407.4 | |
| CDH23 | NM_001171933.1 | c.1103G>A | p.Arg368His | missense_variant | 8/23 | NP_001165404.1 | ||
| CDH23 | NM_001171934.1 | c.1103G>A | p.Arg368His | missense_variant | 8/22 | NP_001165405.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000572 AC: 87AN: 151976Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000667 AC: 150AN: 224942Hom.: 0 AF XY: 0.000631 AC XY: 77AN XY: 122086
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GnomAD4 exome AF: 0.000698 AC: 1011AN: 1448356Hom.: 1 Cov.: 34 AF XY: 0.000673 AC XY: 484AN XY: 719238
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GnomAD4 genome 0.000572 AC: 87AN: 152094Hom.: 0 Cov.: 31 AF XY: 0.000605 AC XY: 45AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:14Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:4Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 11, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 05, 2021 | This variant is associated with the following publications: (PMID: 16963483, 21940737, 12786748, 28847902, 27018795, 12075507, 19683999, 21174530, 26969326, 30459346, 33576794) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 10, 2016 | - - |
| Likely pathogenic, flagged submission | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Usher syndrome type 1D Uncertain:2
| Uncertain significance, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The CDH23 c.7823G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3. Based on this evidence we have classified this variant as Variant of Uncertian Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | research | UAEU Genomics Laboratory, United Arab Emirates University | Dec 21, 2021 | The missense variant NM_022124.6(CDH23):c.7823G>A (p.Arg2608His) has been reported in compound heterozygous state in multiple publications in individuals affected with nonsyndromic deafness (PMID: 12075507, PubMed: 26969326, PMID: 27018795) Usher syndrome (PMID: 33576794, PMID: 19683999) in at least 4 individuals with a likely pathogenic or rare allele (PubMed: 33576794, PMID: 30459346, PMID: 12075507, PubMed: 26969326). This variant was also present in heterozygous state in individuals affected with non-syndromic sensorineural hearing loss (PMID: 30459346, PMID: 27018795). Another variant causing a different amino acid change (p.Arg2608Cys)) has been reported in an individual with nonsyndromic recessive deafness, who also had another variant in the same gene in homozygous state (PubMeD: 26226137). The p.Arg2608His variant is observed in 107/99,932 (0.1071%) alleles from individuals of gnomAD Non Finnish European background in gnomAD database, which is higher than that specified by the hearing loss expert working group (PubMed: 30311386). Computational prediction tools and conservation analysis indicate that this change could be deleterious. Structural modeling studies indicated that this variant affect one of the outward facing residues in the CDH23 extracellular domain and might affect intramolecular hydrogen bonding and cis- dimer formation (PMID: 30033219). In summary, though the variant has been reported frequently patients with disease, the available evidence is insufficient to classify this variant with certainty. For these reasons, this variant has been classified as Uncertain significance. - |
Retinal dystrophy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: CDH23 c.7823G>A (p.Arg2608His) results in a non-conservative amino acid change located in the cadherin repeat region (IPR002126) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 1,593,492 control chromosomes in the gnomAD database (v4.0 dataset), including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in CDH23 causing Usher Syndrome (0.0032), allowing no conclusion about variant significance. c.7823G>A has been reported in the literature in compound heterozygous state together with a second pathogenic variant (though in most of these cases the phase was not specified) in individuals affected with Usher Syndrome (e.g. Jaijo_2009, Colombo_2021), nonsyndromic hearing loss (Astuto_2002, Wu_2016), and retinal disease (Zampaglione_2022). On the other hand, the variant has been reported in homozygous state in a patient affected with retinal disease (without hearing loss), who carried a homozygous pathogenic variant in another gene, which could explain the phenotype (Ortube_2014). The variant has been also reported in (apparent) heterozygosity in affected individuals in whom a second (likely) pathogenic mutation was not identified (e.g. Fuster-Garcia_2018, Mansard_2021, Wu_2016, Sloan-Heggen_2016), however, in one of these cases co-occurring pathogenic variants could explain the phenotype (Mansard_2021). In many of the reported cases, the CDH23 gene was not completely sequenced, or other genes and large rearrangements were not assessed, thus these reports do not provide conclusive evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12075507, 27018795, 26969326, 19683999, 30459346, 33576794, 34948090, 24444108, 36460718, 34906470). 13 submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant with conflicting assessments, i.e. as likely pathogenic (n=2), VUS (n=9), or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Neurodevelopmental abnormality Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Apr 03, 2020 | - - |
CDH23-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The CDH23 c.7823G>A (p.Arg2608His) missense variant has been reported in at least three studies in individuals with autosomal recessive nonsyndromic hearing loss, in which it is found in a total of 25 individuals, including in three in a compound heterozygous state and in 22 in a heterozygous state (Astuto et al. 2002; Wu et al. 2016). The p.Arg2608His variant is also reported in one study in a compound heterozygous state in an individual with Usher syndrome (Jaijo et al. 2010). The p.Arg2608His variant was absent from 256 controls, but is reported at a frequency of 0.00213 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg2608His variant is classified as a variant of unknown significance but suspicious for pathogenicity for CDH23-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pituitary adenoma 5, multiple types Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 06, 2023 | - - |
Retinitis pigmentosa-deafness syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Rare genetic deafness Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2022 | The p.Arg2608His variant in CDH23 has been reported in 0.1% (7/6982) of chromosomes from probands with either hearing loss or Usher syndrome, at least one of whom had an alternate genetic cause for their disease (Astuto 2002, Jaijo 2010; Malm 2011, LMM data). However, this variant has also been identified in 0.1% (116/115288) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which suggests that the variant is unlikely to be causative for disease. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of p.Arg2608His is uncertain, these data suggest that it is more likely benign. ACMG/AMP criteria: BS1_Supporting, PP3. - |
Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 01-06-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;N
REVEL
Uncertain
Sift
Benign
.;.;.;T
Sift4G
Uncertain
D;.;D;D
Polyphen
1.0
.;D;.;.
Vest4
MVP
MPC
0.45
ClinPred
T
GERP RS
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gMVP
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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