rs199537178
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001384140.1(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 (★★).
Frequency
Consequence
NM_001384140.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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PCDH15 | ENST00000320301.11 | c.2102C>T | p.Ala701Val | missense_variant | Exon 18 of 33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.2102C>T | p.Ala701Val | missense_variant | Exon 18 of 38 | NM_001384140.1 | ENSP00000495195.1 |
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
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not provided Uncertain:2
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. -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported without a second PCDH15 variant in a proband with bilateral sensorineural hearing loss who also had multiple variants in other hearing loss-associated genes (PMID: 29907799); This variant is associated with the following publications: (PMID: 15537665, 29907799) -
not specified Uncertain:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at