rs369396703
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3PP4PM3
This summary comes from the ClinGen Evidence Repository: The c.1515-12G>A variant in CDH23 is an intronic variant which is located in intron 15. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009% ( 2/21986) in the African/African American population (PM2_supporting, BS1, and BA1 not met). The results from 3 in silico splicing predictors including MaxEntScan indicate that this variant may affect splicing by disrupting the acceptor splice site (PP3). This variant has been detected in 3 individuals with hearing loss and 2 individuals with Usher syndrome. The individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed in trans (PM3, PP4, SCV000564845.4, SCV000804605.2). In summary, this variant is classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10.18.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5543878/MONDO:0019501/005
Frequency
Consequence
NM_022124.6 splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1515-12G>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000224721.12 | |||
CDH23 | NM_001171930.2 | c.1515-12G>A | splice_polypyrimidine_tract_variant, intron_variant | ||||
CDH23 | NM_001171931.2 | c.1515-12G>A | splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1515-12G>A | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000221 AC: 5AN: 226432Hom.: 0 AF XY: 0.0000164 AC XY: 2AN XY: 122234
GnomAD4 exome AF: 0.0000146 AC: 21AN: 1438586Hom.: 0 Cov.: 31 AF XY: 0.00000983 AC XY: 7AN XY: 712028
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74254
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2021 | Identified with a second CDH23 variant in patients with bilateral sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (Cesca et al., 2020); In silico analysis supports a deleterious effect on splicing; Classified as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (ClinVar SCV001245157.1; Oza et al., 2018); This variant is associated with the following publications: (PMID: 32467589) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2022 | This sequence change falls in intron 15 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. This variant is present in population databases (rs369396703, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 32467589). ClinVar contains an entry for this variant (Variation ID: 228484). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Pituitary adenoma 5, multiple types Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2023 | - - |
Nonsyndromic genetic hearing loss Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Jul 15, 2021 | Already curated by HL expert panel. The allele frequency of the c.1515-12G>A variant in the CDH23 gene is 0.01% (1/9692) of Ashkenazi Jewish chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). Computational prediction tools and conservation analysis suggest that the c.1515-12G>A variant may impact splicing (PP3). This variant was reported in two patients with Usher syndrome (GeneDx unpublished data SCV000564845.2, Human Genetics Radboudumc unpublished data SCV000804605.2) and one with sloping sensorineural hearing loss (LMM unpublished data SCV000271550.2). The probands with Usher syndrome had a suspected-pathogenic variant in CDH23 with an unknown phase (PM3; SCV000564845.2, SCV000804605.2). In this study, two siblings with non-sydromic hearing loss (high frequencies affected )carried this variant in trans with A366T applying to PP1_Sup. In summary, the clinical significance of this variant is Likely Pathogenic based on the ACMG/AMP and gene-specific hearing loss Expert panel standars and guidelines (PM2_Supporting, PM3, PP3, PP1_Sup) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 11, 2015 | The c.1515-12G>A variant in CDH23 has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 1/26694 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; rs369396703). Although this variant has been seen in the general popu lation, its frequency is not high enough to rule out a pathogenic role. This var iant is located in the 3' splice region. Computational tools suggest an impact to splicing. However, this information is not predictive enough to determine pat hogenicity. In summary, the clinical significance of the c.1515-12G>A variant is uncertain. - |
Usher syndrome Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Oct 18, 2023 | The c.1515-12G>A variant in CDH23 is an intronic variant which is located in intron 15. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009% ( 2/21986) in the African/African American population (PM2_supporting, BS1, and BA1 not met). The results from 3 in silico splicing predictors including MaxEntScan indicate that this variant may affect splicing by disrupting the acceptor splice site (PP3). This variant has been detected in 3 individuals with hearing loss and 2 individuals with Usher syndrome. The individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed in trans (PM3, PP4, SCV000564845.4, SCV000804605.2). In summary, this variant is classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10.18.2023). - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 10, 2020 | - - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at