rs555432123
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_022124.6(CDH23):c.5945A>G(p.Asn1982Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,852 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
1
6
8
Clinical Significance
Conservation
PhyloP100: 9.06
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=0.20081562).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.5945A>G | p.Asn1982Ser | missense_variant | 46/70 | ENST00000224721.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.5945A>G | p.Asn1982Ser | missense_variant | 46/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000728 AC: 18AN: 247390Hom.: 0 AF XY: 0.0000521 AC XY: 7AN XY: 134432
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461550Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22AN XY: 727082
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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 provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2016 | The N1982S variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The N1982S variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N1982S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N1982S as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1982 of the CDH23 protein (p.Asn1982Ser). This variant is present in population databases (rs555432123, gnomAD 0.03%). This missense change has been observed in individual(s) with hearing loss (PMID: 31152317). ClinVar contains an entry for this variant (Variation ID: 422021). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. - |
Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;.
Polyphen
0.99
.;D
Vest4
MutPred
Gain of glycosylation at N1982 (P = 0.0035);Gain of glycosylation at N1982 (P = 0.0035);
MVP
ClinPred
T
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