rs727502931
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_022124.6(CDH23):c.7362+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000274 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CDH23
NM_022124.6 splice_donor_5th_base, intron
NM_022124.6 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9975
2
Clinical Significance
Conservation
PhyloP100: 4.07
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 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
?
Variant 10-71799634-G-A is Pathogenic according to our data. Variant chr10-71799634-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71799634-G-A is described in Lovd as [Pathogenic]. Variant chr10-71799634-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.7362+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000224721.12 | |||
CDH23 | NM_001171933.1 | c.642+5G>A | splice_donor_5th_base_variant, intron_variant | ||||
CDH23 | NM_001171934.1 | c.642+5G>A | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.7362+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249264Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135226
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461692Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727130
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 1D Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Apr 21, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Pituitary adenoma 5, multiple types Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 29, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change falls in intron 52 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs727502931, gnomAD 0.01%). This variant has been observed in individual(s) with Usher syndrome (PMID: 11138009, 11857743, 23591405). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS51+5G>A. ClinVar contains an entry for this variant (Variation ID: 4918). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 52, but is expected to preserve the integrity of the reading-frame (PMID: 11138009). For these reasons, this variant has been classified as Pathogenic. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 25, 2013 | The 7362+5G>A variant in CDH23 has been identified in three German individuals w ith Usher syndrome who were either homozygous or had a second variant in CDH23, and was not observed in at least 400 ethnically matched chromosomes (Bolz 2001, von Brederlow 2002, Glockle 2013). In addition, this variant is located in the c onserved 5' splice region, and functional analyses using RT-PCR reveal that the variant causes an in-frame skipping of exon 52 (Bolz 2001). In summary, this var iant meets our criteria to be classified as pathogenic (http://pcpgm.partners.or g/LMM) based upon its presence in individuals with Usher syndrome and its observ ed impact on splicing. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at