10-71799634-G-A
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 region, 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
Consequence
NM_022124.6 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.7362+5G>A | splice_region_variant, intron_variant | Intron 52 of 69 | ENST00000224721.12 | NP_071407.4 | ||
CDH23 | NM_001171933.1 | c.642+5G>A | splice_region_variant, intron_variant | Intron 5 of 22 | NP_001165404.1 | |||
CDH23 | NM_001171934.1 | c.642+5G>A | splice_region_variant, intron_variant | Intron 5 of 21 | NP_001165405.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249264Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135226
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461692Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727130
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Usher syndrome type 1D Pathogenic:2
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Pituitary adenoma 5, multiple types Pathogenic:1
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not provided Pathogenic:1
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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at