rs781716568
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_022124.6(CDH23):āc.9883A>Cā(p.Thr3295Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,611,174 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3295S) has been classified as Uncertain significance.
Frequency
Consequence
NM_022124.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.9883A>C | p.Thr3295Pro | missense_variant | 70/70 | ENST00000224721.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.9883A>C | p.Thr3295Pro | missense_variant | 70/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152258Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000373 AC: 9AN: 241150Hom.: 0 AF XY: 0.0000455 AC XY: 6AN XY: 131926
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1458798Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 725628
GnomAD4 genome ? AF: 0.0000656 AC: 10AN: 152376Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 8AN XY: 74522
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 3295 of the CDH23 protein (p.Thr3295Pro). This variant is present in population databases (rs781716568, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 228511). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDH23 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 30, 2015 | The p.Thr3295Pro variant in CDH23 has not been previously reported in individual s with hearing loss, but has been identified in 3/10434 of Latino chromosomes an d 1/58040 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs368112637). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr3295Pro variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2022 | The c.9883A>C (p.T3295P) alteration is located in exon 70 (coding exon 69) of the CDH23 gene. This alteration results from a A to C substitution at nucleotide position 9883, causing the threonine (T) at amino acid position 3295 to be replaced by a proline (P). 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. | Oct 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at