rs121908349
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_022124.6(CDH23):c.6604G>A(p.Asp2202Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_022124.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248868Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135028
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461490Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727044
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74272
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Pathogenic:1
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Pituitary adenoma 5, multiple types Pathogenic:1
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Usher syndrome Pathogenic:1
Variant summary: CDH23 c.6604G>A (p.Asp2202Asn) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248868 control chromosomes (gnomAD). c.6604G>A has been reported in the literature in bi-allelic individuals affected with autosomal recessive non syndromic hearing loss (examples: Schultz_2011, Kim_2016, Chen_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21940737, 31445392, 11090341, 35020051, 27792758, 27018795). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Usher syndrome type 1 Pathogenic:1
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not provided Pathogenic:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2202 of the CDH23 protein (p.Asp2202Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 11090341, 21940737, 31445392, 35020051). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as D1400N. ClinVar contains an entry for this variant (Variation ID: 4920). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDH23 protein function. For these reasons, this variant has been classified as Pathogenic. -
Hearing loss, autosomal recessive Pathogenic:1
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Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at