rs41281304
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+76C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00667 in 1,613,580 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0051 ( 7 hom., cov: 33)
Exomes 𝑓: 0.0068 ( 46 hom. )
Consequence
CDH23
NM_022124.6 intron
NM_022124.6 intron
Scores
1
12
Clinical Significance
Conservation
PhyloP100: 0.211
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=0.0049705207).
BP6
Variant 10-71646693-C-A is Benign according to our data. Variant chr10-71646693-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 45871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71646693-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00506 (771/152278) while in subpopulation NFE AF= 0.00819 (557/68026). AF 95% confidence interval is 0.00763. There are 7 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 AD,AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1449+76C>A | intron_variant | ENST00000224721.12 | NP_071407.4 | |||
CDH23 | NM_052836.4 | c.1525C>A | p.Pro509Thr | missense_variant | 14/14 | NP_443068.1 | ||
CDH23 | NM_001171930.2 | c.1449+76C>A | intron_variant | NP_001165401.1 | ||||
CDH23 | NM_001171931.2 | c.1449+76C>A | intron_variant | NP_001165402.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1449+76C>A | intron_variant | 5 | NM_022124.6 | ENSP00000224721 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00506 AC: 770AN: 152160Hom.: 7 Cov.: 33
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GnomAD3 exomes AF: 0.00440 AC: 1090AN: 247500Hom.: 3 AF XY: 0.00440 AC XY: 592AN XY: 134408
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GnomAD4 exome AF: 0.00683 AC: 9984AN: 1461302Hom.: 46 Cov.: 31 AF XY: 0.00660 AC XY: 4794AN XY: 726860
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GnomAD4 genome AF: 0.00506 AC: 771AN: 152278Hom.: 7 Cov.: 33 AF XY: 0.00478 AC XY: 356AN XY: 74470
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 08, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 11, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2020 | This variant is associated with the following publications: (PMID: 32707200) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | CDH23: BP4, BS2 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 30, 2013 | Pro509Thr in exon 14 of CDH23: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (56/8306) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs41281304). - |
Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 23, 2021 | - - |
CDH23-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N
REVEL
Benign
Sift4G
Pathogenic
D;D
Polyphen
B;.
Vest4
MVP
ClinPred
T
GERP RS
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