rs750803248
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_022124.6(CDH23):c.1428dup(p.Thr477AspfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
CDH23
NM_022124.6 frameshift
NM_022124.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.46
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-71646592-T-TG is Pathogenic according to our data. Variant chr10-71646592-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 423771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1428dup | p.Thr477AspfsTer10 | frameshift_variant | 14/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.1428dup | p.Thr477AspfsTer10 | frameshift_variant | 14/32 | ||
CDH23 | NM_001171931.2 | c.1428dup | p.Thr477AspfsTer10 | frameshift_variant | 14/26 | ||
CDH23 | NM_052836.4 | c.1428dup | p.Thr477AspfsTer48 | frameshift_variant | 14/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1428dup | p.Thr477AspfsTer10 | frameshift_variant | 14/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249290Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135242
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727138
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 26, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 423771). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. This variant is present in population databases (rs750803248, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Thr477Aspfs*10) in the CDH23 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH23 are known to be pathogenic (PMID: 11138009, 21940737). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2017 | The c.1428dupG variant in the CDH23 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1428dupG variant causes a frameshift starting with codon Threonine 477, changes this amino acid to an Aspartic acid residue, and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Thr477AspfsX10. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1428dupG variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1428dupG as a pathogenic variant. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2017 | - - |
Pituitary adenoma 5, multiple types Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 10, 2022 | - - |
Usher syndrome type 1D Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Dec 02, 2021 | - - |
Computational scores
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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