rs73275848
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_022124.6(CDH23):c.3580-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 1,612,894 control chromosomes in the GnomAD database, including 1,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.049 ( 615 hom., cov: 33)
Exomes 𝑓: 0.0051 ( 590 hom. )
Consequence
CDH23
NM_022124.6 intron
NM_022124.6 intron
Scores
2
Splicing: ADA: 0.00002238
2
Clinical Significance
Conservation
PhyloP100: -1.65
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]
C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
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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=-0.83).
BP6
Variant 10-71730457-C-T is Benign according to our data. Variant chr10-71730457-C-T is described in ClinVar as [Benign]. Clinvar id is 45924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71730457-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDH23 | NM_022124.6 | c.3580-12C>T | intron_variant | ENST00000224721.12 | NP_071407.4 | |||
| CDH23 | NM_001171930.2 | c.3580-12C>T | intron_variant | NP_001165401.1 | ||||
| C10orf105 | NM_001168390.2 | c.-6+7271G>A | intron_variant | NP_001161862.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CDH23 | ENST00000224721.12 | c.3580-12C>T | intron_variant | 5 | NM_022124.6 | ENSP00000224721.9 |
Frequencies
GnomAD3 genomes 0.0490 AC: 7460AN: 152114Hom.: 616 Cov.: 33
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GnomAD3 exomes AF: 0.0121 AC: 2996AN: 247868Hom.: 233 AF XY: 0.00915 AC XY: 1232AN XY: 134596
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GnomAD4 exome AF: 0.00509 AC: 7435AN: 1460664Hom.: 590 Cov.: 31 AF XY: 0.00436 AC XY: 3166AN XY: 726572
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GnomAD4 genome 0.0491 AC: 7470AN: 152230Hom.: 615 Cov.: 33 AF XY: 0.0470 AC XY: 3500AN XY: 74442
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 24, 2011 | 3580-12C>T in intron 31 of CDH23: This variant is not expected to have clinical significance because it has been identified in 19.5% (23/118) African control ch romosomes and 6% (54/900) general population chromosomes (rs73275848). Furthermo re, this variant is not expected to have clinical significance because it is not located in the conserved region of the splicing consensus sequence. - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Usher syndrome type 1D Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Autosomal recessive nonsyndromic hearing loss 12 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
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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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