rs121908351
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_022124.6(CDH23):c.4021G>A(p.Asp1341Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
10
4
3
Clinical Significance
Conservation
PhyloP100: 9.61
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_pathogenic. Variant got 9 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.836
PP5
Variant 10-71732292-G-A is Pathogenic according to our data. Variant chr10-71732292-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71732292-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.4021G>A | p.Asp1341Asn | missense_variant | 32/70 | ENST00000224721.12 | NP_071407.4 | |
CDH23 | NM_001171930.2 | c.4021G>A | p.Asp1341Asn | missense_variant | 32/32 | NP_001165401.1 | ||
C10orf105 | NM_001168390.2 | c.-6+5436C>T | intron_variant | NP_001161862.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.4021G>A | p.Asp1341Asn | missense_variant | 32/70 | 5 | NM_022124.6 | ENSP00000224721 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000407 AC: 1AN: 245970Hom.: 0 AF XY: 0.00000749 AC XY: 1AN XY: 133504
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GnomAD4 exome AF: 0.00000959 AC: 14AN: 1460280Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 726278
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12075507, 19683999, 16963483, 12786748, 21940737, 31589614, 35020051, 15353998, 12522556) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 23, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1341 of the CDH23 protein (p.Asp1341Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive non-syndromic hearing loss and with Usher syndrome (PMID: 12522556, 19683999). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4923). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDH23 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pituitary adenoma 5, multiple types Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 05, 2023 | Variant summary: CDH23 c.4021G>A (p.Asp1341Asn) results in a conservative amino acid change in 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 4.1e-06 in 245970 control chromosomes. c.4021G>A has been reported at a compound heterozygous state along with different pathogenic variants in CDH23 in multiple individuals affected with autosomal recessive hearing loss (example, Usami_2022, deBrouwer_2003). These data indicate that the variant is very likely to be associated with disease. 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: 35020051, 12522556). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Usher syndrome type 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2003 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;H;.
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
REVEL
Pathogenic
Sift4G
Pathogenic
D;D;.;D
Polyphen
1.0
.;.;D;.
Vest4
MVP
ClinPred
D
GERP RS
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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