rs397517362
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_022124.6(CDH23):c.8781C>A(p.Tyr2927Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CDH23
NM_022124.6 stop_gained
NM_022124.6 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.85
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 10-71809878-C-A is Pathogenic according to our data. Variant chr10-71809878-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 46053.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.8781C>A | p.Tyr2927Ter | stop_gained | 61/70 | ENST00000224721.12 | |
LOC124902446 | XR_007062185.1 | n.2015G>T | non_coding_transcript_exon_variant | 2/2 | |||
CDH23 | NM_001171933.1 | c.2061C>A | p.Tyr687Ter | stop_gained | 14/23 | ||
CDH23 | NM_001171934.1 | c.2061C>A | p.Tyr687Ter | stop_gained | 14/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.8781C>A | p.Tyr2927Ter | stop_gained | 61/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 46053). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr2927*) 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). - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 26, 2012 | The Tyr2927X variant in CDH23 has not been reported in the literature nor previo usly identified by our laboratory. This nonsense variant leads to a premature te rmination codon at position 2927, which is predicted to lead to a truncated or a bsent protein. In summary, this variant meets our criteria to be classified as p athogenic (http://pcpgm.partners.org/LMM). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at