10-71812781-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_022124.6(CDH23):c.9524G>A(p.Arg3175His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3175C) has been classified as Likely benign.
Frequency
Consequence
NM_022124.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.9524G>A | p.Arg3175His | missense_variant | 68/70 | ENST00000224721.12 | |
LOC124902446 | XR_007062185.1 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.9524G>A | p.Arg3175His | missense_variant | 68/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000269 AC: 41AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000279 AC: 69AN: 246978Hom.: 0 AF XY: 0.000321 AC XY: 43AN XY: 134030
GnomAD4 exome AF: 0.000220 AC: 322AN: 1460780Hom.: 0 Cov.: 38 AF XY: 0.000231 AC XY: 168AN XY: 726576
GnomAD4 genome AF: 0.000269 AC: 41AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 19, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | CDH23: PM2, PP3 - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 29, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 25, 2023 | Variant summary: CDH23 c.9524G>A (p.Arg3175His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 246978 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.00028 vs 0.0032), allowing no conclusion about variant significance. c.9524G>A has been reported in the literature in individuals affected with Usher Syndrome or non-syndromic hearing loss (e.g. Astuto_2002, Usami_2008, Cabanillas_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Yonezawa_2006, Takahashi_2016), suggesting that the variant does not alter protein localization but may impact microtubule formation. However, these findings do not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 12075507, 29986705, 27349180, 18368581, 16281288). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2017 | - - |
Pituitary adenoma 5, multiple types Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 02, 2022 | - - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 03, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at