rs201053044
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_022124.6(CDH23):c.3022G>A(p.Val1008Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,607,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict 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. V1008V) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.3022G>A | p.Val1008Met | missense_variant | 26/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.3022G>A | p.Val1008Met | missense_variant | 26/32 | ||
CDH23 | NM_001171931.2 | c.3022G>A | p.Val1008Met | missense_variant | 26/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.3022G>A | p.Val1008Met | missense_variant | 26/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000381 AC: 58AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000187 AC: 44AN: 235742Hom.: 0 AF XY: 0.000148 AC XY: 19AN XY: 127998
GnomAD4 exome AF: 0.000254 AC: 369AN: 1455004Hom.: 0 Cov.: 31 AF XY: 0.000232 AC XY: 168AN XY: 722978
GnomAD4 genome ? AF: 0.000381 AC: 58AN: 152320Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27AN XY: 74468
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2016 | The V1008M variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed at any significant frequency in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V1008M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V1008M as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 18, 2014 | - - |
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 | Oct 31, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 24, 2019 | Variant classified as Uncertain Significance - Favor Benign. The p.Val1008Met variant in CDH23 has not been previously reported in individuals with hearing loss, but was reported in ClinVar (Variation ID 166811). This variant was also identified in several populations in gnomAD, with the highest allele frequency observed in 0.25% (25/10040) of Ashkenazi Jewish chromosomes (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. - |
Pituitary adenoma 5, multiple types Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 19, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | The c.3022G>A (p.V1008M) alteration is located in exon 26 (coding exon 25) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 3022, causing the valine (V) at amino acid position 1008 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 13, 2020 | - - |
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. - |
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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at