chr10-54185235-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_033056.4(PCDH15):c.1339G>A(p.Asp447Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,613,308 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.1339G>A | p.Asp447Asn | missense_variant | 12/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.1339G>A | p.Asp447Asn | missense_variant | 12/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.1339G>A | p.Asp447Asn | missense_variant | 12/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.1339G>A | p.Asp447Asn | missense_variant | 12/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes AF: 0.000342 AC: 52AN: 151922Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000203 AC: 51AN: 251296Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135806
GnomAD4 exome AF: 0.000500 AC: 730AN: 1461386Hom.: 1 Cov.: 31 AF XY: 0.000488 AC XY: 355AN XY: 727000
GnomAD4 genome AF: 0.000342 AC: 52AN: 151922Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74204
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | PCDH15: PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 447 of the PCDH15 protein (p.Asp447Asn). This variant is present in population databases (rs150509146, gnomAD 0.04%). 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: 46441). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 01, 2017 | The p.Asp447Asn variant (rs150509146) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 46441). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.044% (identified in 56 out of 126,490 chromosomes). The aspartic acid at codon 447 is weakly conserved considering 12 species (Alamut software v2.9), and several species of fish have an asparagine at this position suggesting this change is evolutionary tolerated. Likewise, computational analyses suggest this variant does not have a significant effect on PCDH15 protein structure/function (SIFT: tolerated, PolyPhen2: benign). However, based on the available information, the clinical significance of the p.Asp447Asn variant cannot be determined with certainty. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 30, 2022 | BP4, PM2_supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2022 | 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; This variant is associated with the following publications: (PMID: 15537665) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 11, 2014 | The Asp447Asn variant in PCDH15 has been previously reported by our laboratory i n 1 individual with hearing loss and delayed walking, but a variant affecting th e remaining copy of PCDH15 was not identified. This variant has been identified in 0.06% (5/8600) of European American chromosomes by the NHLBI Exome Sequencin g Project and in 0.7% (1/1324) chromosomes by the ClinSeq project (http://evs.gs .washington.edu/EVS/; dbSNP rs150509146). Computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Asp447Asn variant is uncertain. - |
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 | Feb 11, 2022 | - - |
Usher syndrome type 1F Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 17, 2020 | - - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at