rs796051861
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_022124.6(CDH23):βc.193delβ(p.Leu65TrpfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.000012 ( 0 hom. )
Consequence
CDH23
NM_022124.6 frameshift
NM_022124.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.95
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 10-71510124-AC-A is Pathogenic according to our data. Variant chr10-71510124-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 4925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71510124-AC-A is described in Lovd as [Pathogenic]. Variant chr10-71510124-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.193del | p.Leu65TrpfsTer49 | frameshift_variant | 4/70 | ENST00000224721.12 | |
CDH23-AS1 | NR_120672.1 | n.144-115del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.193del | p.Leu65TrpfsTer49 | frameshift_variant | 4/70 | 5 | NM_022124.6 | P1 | |
CDH23-AS1 | ENST00000428918.1 | n.97-115del | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727136
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31
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727136
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2016 | The c.193delC variant in the CDH23 gene has been reported previously in the compound heterozygous state with a second pathogenic variant in an individual with atypical Usher syndrome (Astuto et al., 2002). The c.193delC variant causes a frameshift starting with codon Leucine 65, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 49 of the new reading frame, denoted p.Leu65TrpfsX49. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.193delC variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.193delC as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2023 | This sequence change creates a premature translational stop signal (p.Leu65Trpfs*49) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 12075507). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4925). For these reasons, this variant has been classified as Pathogenic. - |
Usher syndrome type 1D Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2005 | - - |
USHER SYNDROME, TYPE ID/F, DIGENIC Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2005 | - - |
Usher syndrome type 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
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