rs201076440
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_022124.6(CDH23):c.8311G>A(p.Gly2771Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,613,678 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00061 ( 1 hom. )
Consequence
CDH23
NM_022124.6 missense, splice_region
NM_022124.6 missense, splice_region
Scores
5
6
4
Clinical Significance
Conservation
PhyloP100: 9.96
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 | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.8311G>A | p.Gly2771Ser | missense_variant, splice_region_variant | 59/70 | ENST00000224721.12 | |
CDH23 | NM_001171933.1 | c.1591G>A | p.Gly531Ser | missense_variant, splice_region_variant | 12/23 | ||
CDH23 | NM_001171934.1 | c.1591G>A | p.Gly531Ser | missense_variant, splice_region_variant | 12/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.8311G>A | p.Gly2771Ser | missense_variant, splice_region_variant | 59/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000355 AC: 54AN: 152156Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000391 AC: 97AN: 247830Hom.: 1 AF XY: 0.000364 AC XY: 49AN XY: 134588
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GnomAD4 exome AF: 0.000608 AC: 888AN: 1461404Hom.: 1 Cov.: 32 AF XY: 0.000572 AC XY: 416AN XY: 726946
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2020 | Observed heterozygous in an individual with Usher syndrome without a second variant identified in published literature (Oshima et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32707200, 30245029, 18429043) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2771 of the CDH23 protein (p.Gly2771Ser). This variant is present in population databases (rs201076440, gnomAD 0.07%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 18429043). ClinVar contains an entry for this variant (Variation ID: 177767). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
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 | - | - - |
Hearing impairment Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PS1_Strong, PM2_Supporting, PP3_Supporting, BS2_Supporting - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 26, 2013 | The Gly2771Ser variant in CDH23 has been previously reported in the heterozygous state in one individual with Usher syndrome; however, a second variant in CDH23 was not identified (Oshima 2008). This variant has been identified in 0.06% (5/ 8412) of European American chromosomes by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS/; dbSNP rs201076440); however, this frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. In summary, addit ional data is needed to determine the clinical significance of this variant. - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;.;D;D
Polyphen
1.0
.;D;.;.
Vest4
MVP
MPC
0.62
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at