rs41281314
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_022124.6(CDH23):c.3625A>G(p.Thr1209Ala) variant causes a missense change. The variant allele was found at a frequency of 0.008 in 1,613,916 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.042 ( 462 hom., cov: 33)
Exomes 𝑓: 0.0044 ( 444 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
4
10
Clinical Significance
Conservation
PhyloP100: 6.15
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=0.0019724965).
BP6
?
Variant 10-71730514-A-G is Benign according to our data. Variant chr10-71730514-A-G is described in ClinVar as [Benign]. Clinvar id is 4927.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-71730514-A-G is described in Lovd as [Benign]. Variant chr10-71730514-A-G is described in Lovd as [Likely_benign].
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.3625A>G | p.Thr1209Ala | missense_variant | 31/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.3625A>G | p.Thr1209Ala | missense_variant | 31/32 | ||
C10orf105 | NM_001168390.2 | c.-6+7214T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.3625A>G | p.Thr1209Ala | missense_variant | 31/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0425 AC: 6466AN: 152180Hom.: 463 Cov.: 33
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GnomAD3 exomes AF: 0.0105 AC: 2625AN: 249000Hom.: 173 AF XY: 0.00785 AC XY: 1061AN XY: 135150
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GnomAD4 exome AF: 0.00440 AC: 6438AN: 1461618Hom.: 444 Cov.: 31 AF XY: 0.00376 AC XY: 2731AN XY: 727086
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GnomAD4 genome ? AF: 0.0425 AC: 6472AN: 152298Hom.: 462 Cov.: 33 AF XY: 0.0407 AC XY: 3033AN XY: 74470
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:12Other:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 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. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 03, 2010 | Thr1209Ala in exon 31 of CDH23: This variant has been identified in over 20% of a Black population (dbSNP rs41281314) and is therefore classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2021 | Variant summary: CDH23 c.3625A>G (p.Thr1209Ala) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 249000 control chromosomes, predominantly at a frequency of 0.14 within the African or African-American subpopulation in the gnomAD database, including 170 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 43.38 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing Usher Syndrome phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 10, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:3Other:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 23, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not provided, no classification provided | literature only | NEI Ophthalmic Genomics Laboratory, National Institutes of Health | - | - - |
Usher syndrome type 1 Benign:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Jan 12, 2011 | - - |
Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 05, 2022 | - - |
Usher syndrome Benign:1
Benign, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | May 28, 2019 | The filtering allele frequency (the lower threshold of the 95% CI of 3442/23972) of the c.3625A>G (p.Thr1209Ala) variant in the CDH23 gene is 13.15% for African chromosomes by gnomAD, 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). A splicing assay did not show any impact to splicing but BS3 was not applied given no assessment of protein function (PMID:18273900). Computational prediction analysis using the metapredictor tool REVEL did not predict an impact the protein (BP4). Of note, this variant was reported in 3 patients with Usher syndrome (PMID: 15537665, 15660226, 12075507) though without any convincing evidence for pathogenicity (PM3 not met). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BS3_Supporting, BP4. - |
Autosomal recessive nonsyndromic hearing loss 12 Benign:1
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;.;D
Polyphen
0.57
.;.;P;.
Vest4
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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