rs200798008
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_033056.4(PCDH15):c.709C>T(p.Arg237Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000106 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R237H) has been classified as Uncertain significance.
Frequency
Consequence
NM_033056.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.709C>T | p.Arg237Cys | missense_variant | 8/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.709C>T | p.Arg237Cys | missense_variant | 8/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.709C>T | p.Arg237Cys | missense_variant | 8/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.709C>T | p.Arg237Cys | missense_variant | 8/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 151996Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000917 AC: 23AN: 250784Hom.: 0 AF XY: 0.0000959 AC XY: 13AN XY: 135564
GnomAD4 exome AF: 0.000111 AC: 162AN: 1461572Hom.: 0 Cov.: 32 AF XY: 0.000127 AC XY: 92AN XY: 727100
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 151996Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74210
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 237 of the PCDH15 protein (p.Arg237Cys). This variant is present in population databases (rs200798008, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 164933). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 31, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 31, 2017 | The p.Arg237Cys variant in PCDH15 has been previously identified by our laborato ry in 1 individual with hearing loss without a second PCDH15 variant. This varia nt has also been identified in 15/126086 European chromosomes and 3/10142 Ashken azi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org/; dbSNP rs200798008). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogen ic role. Computational prediction tools and conservation analysis suggest that t he p.Arg237Cys variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, the clinical significanc e of the p.Arg237Cys variant is uncertain. - |
Usher syndrome type 1F Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at