10-71646691-G-T
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_022124.6(CDH23):c.1449+74G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,648 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0082 ( 23 hom., cov: 33)
Exomes 𝑓: 0.00093 ( 22 hom. )
Consequence
CDH23
NM_022124.6 intron
NM_022124.6 intron
Scores
1
11
Clinical Significance
Conservation
PhyloP100: 0.0780
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 (MetaRNN=0.002867937).
BP6
Variant 10-71646691-G-T is Benign according to our data. Variant chr10-71646691-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 46543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71646691-G-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00818 (1246/152286) while in subpopulation AFR AF= 0.0287 (1194/41538). AF 95% confidence interval is 0.0274. There are 23 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 23 AD,AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1449+74G>T | intron_variant | ENST00000224721.12 | NP_071407.4 | |||
CDH23 | NM_052836.4 | c.1523G>T | p.Cys508Phe | missense_variant | 14/14 | NP_443068.1 | ||
CDH23 | NM_001171930.2 | c.1449+74G>T | intron_variant | NP_001165401.1 | ||||
CDH23 | NM_001171931.2 | c.1449+74G>T | intron_variant | NP_001165402.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1449+74G>T | intron_variant | 5 | NM_022124.6 | ENSP00000224721 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00817 AC: 1243AN: 152168Hom.: 23 Cov.: 33
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GnomAD3 exomes AF: 0.00221 AC: 546AN: 247558Hom.: 13 AF XY: 0.00176 AC XY: 237AN XY: 134426
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GnomAD4 exome AF: 0.000929 AC: 1357AN: 1461362Hom.: 22 Cov.: 31 AF XY: 0.000776 AC XY: 564AN XY: 726894
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GnomAD4 genome AF: 0.00818 AC: 1246AN: 152286Hom.: 23 Cov.: 33 AF XY: 0.00771 AC XY: 574AN XY: 74460
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | Cys508Phe in Exon 14 of CDH23: This variant is not expected to have clinical sig nificance because it has been identified in 2.7% (88/3278) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs115450602). - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2018 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
CDH23-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 24, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Calibrated prediction
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BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;N;N
REVEL
Benign
Sift4G
Pathogenic
D;D
Polyphen
P;.
Vest4
MVP
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T
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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