chr10-71802897-G-C
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_022124.6(CDH23):c.7483-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_022124.6 splice_acceptor, intron
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 12Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
- nonsyndromic genetic hearing lossInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Usher syndrome type 1Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Usher syndrome type 1DInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.7483-1G>C | splice_acceptor_variant, intron_variant | Intron 53 of 69 | ENST00000224721.12 | NP_071407.4 | ||
CDH23 | NM_001171933.1 | c.763-1G>C | splice_acceptor_variant, intron_variant | Intron 6 of 22 | NP_001165404.1 | |||
CDH23 | NM_001171934.1 | c.763-1G>C | splice_acceptor_variant, intron_variant | Intron 6 of 21 | NP_001165405.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
ClinVar contains an entry for this variant (Variation ID: 228329). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 53 of the CDH23 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH23 are known to be pathogenic (PMID: 11138009, 21940737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -
Rare genetic deafness Pathogenic:1
The c.7483-1G>C variant in CDH23 has not been previously reported in individuals with hearing loss or in large population studies. This variant occurs in the in variant region (+/- 1,2) of the splice consensus sequence and is predicted to ca use altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) based upon its predicted impact on the protein and low frequency in the general population. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at