rs572222393
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_022124.6(CDH23):c.1134+53C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,588,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
CDH23
NM_022124.6 intron
NM_022124.6 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.18
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 Likely_benign. Variant got -4 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1134+53C>A | intron_variant | ENST00000224721.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1134+53C>A | intron_variant | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000355 AC: 54AN: 152060Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000101 AC: 21AN: 207824Hom.: 0 AF XY: 0.0000709 AC XY: 8AN XY: 112806
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GnomAD4 exome AF: 0.0000292 AC: 42AN: 1436120Hom.: 0 Cov.: 31 AF XY: 0.0000266 AC XY: 19AN XY: 713100
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GnomAD4 genome ? AF: 0.000355 AC: 54AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74406
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 05, 2017 | Variant classified as Uncertain Significance - Favor Benign. The p.Pro396Gln var iant in CDH23 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 0.12% (25/21048) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs572222393). Although this variant has been seen in the general popul ation, its frequency is not high enough to rule out a pathogenic role. Computati onal prediction tools and conservation analyses suggest that this variant may no t impact the protein, though this information is not predictive enough to rule o ut pathogenicity. In summary, while the clinical significance of the p.Pro396Gln variant is uncertain, these data suggest that it is more likely to be benign. A CMG/AMP Criteria applied: BP4 (Richards 2015). - |
Computational scores
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BayesDel_noAF
Benign
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Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at