rs397517328
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_022124.6(CDH23):c.429+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000704 in 1,612,558 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00073 ( 8 hom. )
Consequence
CDH23
NM_022124.6 splice_donor_region, intron
NM_022124.6 splice_donor_region, intron
Scores
1
1
Splicing: ADA: 0.03040
2
Clinical Significance
Conservation
PhyloP100: 2.36
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
?
Variant 10-71511216-G-A is Benign according to our data. Variant chr10-71511216-G-A is described in ClinVar as [Benign]. Clinvar id is 45941.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-71511216-G-A is described in Lovd as [Benign]. Variant chr10-71511216-G-A is described in Lovd as [Likely_pathogenic].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00046 (70/152278) while in subpopulation SAS AF= 0.0139 (67/4824). AF 95% confidence interval is 0.0112. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome at 3 AD,AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.429+4G>A | splice_donor_region_variant, intron_variant | ENST00000224721.12 | |||
CDH23-AS1 | NR_120672.1 | n.143+562C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.429+4G>A | splice_donor_region_variant, intron_variant | 5 | NM_022124.6 | P1 | |||
CDH23-AS1 | ENST00000428918.1 | n.96+562C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000453 AC: 69AN: 152160Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00154 AC: 385AN: 249258Hom.: 3 AF XY: 0.00202 AC XY: 273AN XY: 135234
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GnomAD4 exome AF: 0.000729 AC: 1065AN: 1460280Hom.: 8 Cov.: 40 AF XY: 0.00106 AC XY: 772AN XY: 726518
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ClinVar
Significance: Benign
Submissions summary: Pathogenic:1Uncertain:3Benign:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2019 | This variant is associated with the following publications: (PMID: 30245029, 24416283, 29148562, 30718709) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 08, 2014 | Variant classified as Uncertain Significance - Favor Benign. The 429+4G>A varian t in CDH23 has been previously reported in two Asian families with hearing loss; however, both probands were heterozygous and a variant affecting the remaining CDH23 allele was not identified (LMM unpublished data; Ganapathy 2014). This var iant has not been identified in large population studies, but there is an insuff icient number of Asian chromosomes in these studies to assess the frequency of t he variant in the Asian population. This variant is located in the 5' splice reg ion. Computational tools do not suggest an impact to splicing and this nucleotid e position is not conserved, yet, this information is not predictive enough to r ule out pathogenicity. In summary, while the clinical significance of the 429+4G >A variant is uncertain, these data suggest that is more likely to be benign. - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Nonsyndromic genetic hearing loss Benign:1
Benign, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Jan 15, 2020 | The filtering allele frequency of the c.429+4G>A variant in CDH23 is 1.13% for South Asian chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). This silent variant in CDH23 is not predicted by the computational prediction analysis using MaxEntScan to impact splicing (BP7, BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel (BA1, BP7, BP4). - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at