rs201584731
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_022124.6(CDH23):c.1520C>T(p.Ser507Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000137 in 1,604,760 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S507S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 1 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
3
6
6
Clinical Significance
Conservation
PhyloP100: 6.08
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 -1 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2913933).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1520C>T | p.Ser507Leu | missense_variant | 16/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.1520C>T | p.Ser507Leu | missense_variant | 16/32 | ||
CDH23 | NM_001171931.2 | c.1520C>T | p.Ser507Leu | missense_variant | 16/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1520C>T | p.Ser507Leu | missense_variant | 16/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000134 AC: 32AN: 238658Hom.: 0 AF XY: 0.000132 AC XY: 17AN XY: 129168
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GnomAD4 exome AF: 0.000141 AC: 205AN: 1452534Hom.: 1 Cov.: 31 AF XY: 0.000155 AC XY: 112AN XY: 720962
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GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
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 | Oct 29, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2022 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 507 of the CDH23 protein (p.Ser507Leu). This variant is present in population databases (rs201584731, gnomAD 0.03%). 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: 45876). 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. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 07, 2011 | The Ser507Leu variant in CDH23 has not been reported in the literature nor previ ously identified by our laboratory. This residue is conserved across species and computational analyses (biochemical amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) suggest that the Ser507Leu variant may impact the protein. How ever, this information is not predictive enough to assume pathogenicity. In summ ary, the clinical significance of this variant cannot be determined with certain ty at this time. It should be noted that this lab has only sequenced a limited number of Turkish probands and no Turkish healthy controls. In addition, healthy control information is limited in either public databases or scientific literat ure, such that the full spectrum of benign variation has not yet been defined fo r this population. Future analysis could reveal that the Ser507Leu variant is co mmon in this population and therefore unlikely to be pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2022 | The c.1520C>T (p.S507L) alteration is located in exon 16 (coding exon 15) of the CDH23 gene. This alteration results from a C to T substitution at nucleotide position 1520, causing the serine (S) at amino acid position 507 to be replaced by a leucine (L). 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. | Jan 24, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;.;T;D;.
Polyphen
0.069
.;.;B;.;.;.
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
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