rs143282422
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_022124.6(CDH23):c.1096G>A(p.Ala366Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00923 in 1,613,862 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A366A) has been classified as Likely benign.
Frequency
Consequence
NM_022124.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1096G>A | p.Ala366Thr | missense_variant | 11/70 | ENST00000224721.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1096G>A | p.Ala366Thr | missense_variant | 11/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00653 AC: 994AN: 152146Hom.: 7 Cov.: 32
GnomAD3 exomes AF: 0.00732 AC: 1825AN: 249204Hom.: 22 AF XY: 0.00726 AC XY: 981AN XY: 135174
GnomAD4 exome AF: 0.00952 AC: 13910AN: 1461598Hom.: 128 Cov.: 31 AF XY: 0.00943 AC XY: 6857AN XY: 727090
GnomAD4 genome ? AF: 0.00653 AC: 994AN: 152264Hom.: 7 Cov.: 32 AF XY: 0.00583 AC XY: 434AN XY: 74450
ClinVar
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 30, 2013 | Ala366Thr in Exon 11A of CDH23: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (88/8560) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143282422). - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 24, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 16, 2018 | 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 | Eurofins Ntd Llc (ga) | Jan 13, 2015 | - - |
not provided Benign:6
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 07, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CDH23: BS2 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Nonsyndromic genetic hearing loss Benign:1
Benign, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Jul 15, 2021 | Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria:The filter allele frequency of c.1096 G>A (A366T) in CDH23 gene is 500/10356 (4,5% with 95% CI) in Ashkenazi Jewish ethnic group in gnomad population database, witch meets the criteria for BA1. Computational evidence is not suffcient to apply to PP3 either BP4 (REVEL:0.198). This variant has been identifiec with c.3293A>G in CDH23 gene in an Usher type 1D patient with unkown phase (PMID:18429043 ). Since c.3293A>G is classified as VUS, PM3 is not applied. Also, A366T was detected in hetercygous state in three usher patients without other variants (PMID: 15660226). Considering BA1, the variant is classified as Benign. - |
Usher syndrome type 1 Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 15, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at