rs199537178
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_033056.4(PCDH15):c.2102C>T(p.Ala701Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,613,056 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A701D) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.2102C>T | p.Ala701Val | missense_variant | 18/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.2102C>T | p.Ala701Val | missense_variant | 18/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.2102C>T | p.Ala701Val | missense_variant | 18/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.2102C>T | p.Ala701Val | missense_variant | 18/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000135 AC: 34AN: 250958Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135626
GnomAD4 exome AF: 0.000264 AC: 385AN: 1460938Hom.: 0 Cov.: 30 AF XY: 0.000249 AC XY: 181AN XY: 726802
GnomAD4 genome AF: 0.000112 AC: 17AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74308
ClinVar
Submissions by phenotype
Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 27, 2021 | - - |
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Apr 07, 2015 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 701 of the PCDH15 protein (p.Ala701Val). This variant is present in population databases (rs199537178, 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: 164921). 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 PCDH15 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2023 | 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 | Aug 07, 2015 | The p.Ala701Val variant in PCDH15 has been previously reported by our laboratory in one individual with mild to moderate sensorineural hearing loss; however, a second variant affecting the remaining copy of PCDH15 was not identified in that individual (LMM unpublished data). This variant has been identified in 13/6654 8 European chromosomes by the Exome Aggregation consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs199537178). Computational prediction tools and conserv ation analysis do not provide strong support for or against an impact to the pro tein. In summary, the clinical significance of the p.Ala701Val variant is uncert ain. - |
Usher syndrome type 1F Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at