rs149073355
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_022124.6(CDH23):c.3845A>G(p.Asn1282Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,613,988 control chromosomes in the GnomAD database, including 22 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 0.0033 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0053 ( 21 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
1
7
9
Clinical Significance
Conservation
PhyloP100: 7.22
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.012104154).
BP6
Variant 10-71732116-A-G is Benign according to our data. Variant chr10-71732116-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45931.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=3}. Variant chr10-71732116-A-G is described in Lovd as [Benign]. Variant chr10-71732116-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00529 (7726/1461702) while in subpopulation NFE AF= 0.00647 (7192/1111866). AF 95% confidence interval is 0.00634. There are 21 homozygotes in gnomad4_exome. There are 3668 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 21 AD,AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.3845A>G | p.Asn1282Ser | missense_variant | 32/70 | ENST00000224721.12 | NP_071407.4 | |
CDH23 | NM_001171930.2 | c.3845A>G | p.Asn1282Ser | missense_variant | 32/32 | NP_001165401.1 | ||
C10orf105 | NM_001168390.2 | c.-6+5612T>C | intron_variant | NP_001161862.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.3845A>G | p.Asn1282Ser | missense_variant | 32/70 | 5 | NM_022124.6 | ENSP00000224721.9 |
Frequencies
GnomAD3 genomes AF: 0.00333 AC: 507AN: 152168Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00293 AC: 731AN: 249260Hom.: 1 AF XY: 0.00296 AC XY: 400AN XY: 135236
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GnomAD4 exome AF: 0.00529 AC: 7726AN: 1461702Hom.: 21 Cov.: 31 AF XY: 0.00504 AC XY: 3668AN XY: 727136
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GnomAD4 genome AF: 0.00333 AC: 507AN: 152286Hom.: 1 Cov.: 32 AF XY: 0.00287 AC XY: 214AN XY: 74470
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18429043, 26969326, 24729539, 32707200) - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | CDH23: BS1 - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 02, 2014 | Asn1282Ser in CDH23: This variant is not expected to have clinical significance because it has been identified in 0.5% (40/8452) of European American chromosome s and 0.01% (4/4286) African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS, rs149073355, Oshima 2008). - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 20, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 17, 2022 | Variant summary: CDH23 c.3845A>G (p.Asn1282Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 249260 control chromosomes, predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 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 Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as benign. - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, 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, 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. - |
Meniere disease Uncertain:1
Uncertain significance, criteria provided, single submitter | case-control | Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO) | Jun 21, 2021 | Digenic inheritance along with NM_000260.4:c.1007G>A(MYO7A) - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, 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, 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. - |
Usher syndrome type 1 Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 01, 2020 | - - |
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
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;N;.
PrimateAI
Uncertain
T
REVEL
Uncertain
Sift4G
Uncertain
D;D;.;D
Polyphen
0.93
.;.;P;.
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
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