rs144906721
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_022124.6(CDH23):c.9501G>A(p.Thr3167=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000557 in 1,613,896 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0028 ( 4 hom., cov: 33)
Exomes 𝑓: 0.00033 ( 2 hom. )
Consequence
CDH23
NM_022124.6 synonymous
NM_022124.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.198
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 -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 10-71812600-G-A is Benign according to our data. Variant chr10-71812600-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46074.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=5, Uncertain_significance=2}. Variant chr10-71812600-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.198 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00275 (419/152356) while in subpopulation AFR AF= 0.00928 (386/41578). AF 95% confidence interval is 0.00852. There are 4 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AD,AR,Digenic gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDH23 | NM_022124.6 | c.9501G>A | p.Thr3167= | synonymous_variant | 67/70 | ENST00000224721.12 | NP_071407.4 | |
| LOC124902446 | XR_007062185.1 | n.159C>T | non_coding_transcript_exon_variant | 1/2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CDH23 | ENST00000224721.12 | c.9501G>A | p.Thr3167= | synonymous_variant | 67/70 | 5 | NM_022124.6 | ENSP00000224721 | P1 |
Frequencies
GnomAD3 genomes 0.00275 AC: 419AN: 152238Hom.: 4 Cov.: 33
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GnomAD3 exomes AF: 0.000639 AC: 159AN: 248896Hom.: 0 AF XY: 0.000540 AC XY: 73AN XY: 135112
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GnomAD4 exome AF: 0.000328 AC: 480AN: 1461540Hom.: 2 Cov.: 38 AF XY: 0.000294 AC XY: 214AN XY: 727072
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GnomAD4 genome 0.00275 AC: 419AN: 152356Hom.: 4 Cov.: 33 AF XY: 0.00258 AC XY: 192AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2019 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 06, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | Thr3167Thr in Exon 67 of CDH23: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.6% (21/3282) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144906721). - |
Usher syndrome type 1D Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Atypical Gaucher Disease Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
CDH23-related disorder Benign:1
| Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 15, 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). - |
Combined PSAP deficiency Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Usher syndrome type 1 Benign:1
| Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Galactosylceramide beta-galactosidase deficiency Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Metachromatic leukodystrophy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at