chr10-54213995-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001384140.1(PCDH15):c.1039C>T(p.Leu347Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00397 in 1,612,234 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001384140.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 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.1039C>T | p.Leu347Phe | missense_variant | Exon 10 of 33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.1039C>T | p.Leu347Phe | missense_variant | Exon 10 of 38 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes AF: 0.00315 AC: 480AN: 152182Hom.: 3 Cov.: 33
GnomAD3 exomes AF: 0.00380 AC: 956AN: 251374Hom.: 11 AF XY: 0.00403 AC XY: 548AN XY: 135854
GnomAD4 exome AF: 0.00405 AC: 5913AN: 1459934Hom.: 40 Cov.: 30 AF XY: 0.00416 AC XY: 3019AN XY: 726346
GnomAD4 genome AF: 0.00316 AC: 481AN: 152300Hom.: 3 Cov.: 33 AF XY: 0.00302 AC XY: 225AN XY: 74456
ClinVar
Submissions by phenotype
not specified Benign:5
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p.Leu347Phe in exon 10 of PCDH15: This variant has not been reported in the lite rature but has now been identified by our laboratory in 5/197 (2.5%) individuals with hearing loss yet none of these individuals had a second PCDH15 variant and one family had an alternate cause of hearing loss. In summary, this data sugges ts that the variant is benign. This variant is not expected to have clinical sig nificance, because it has been identified in 355/66702 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 11033436). -
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Variant summary: PCDH15 c.1039C>T (p.Leu347Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0038 in 251374 control chromosomes, predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.1039C>T in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments and a majority consensus as Benign (n=4) (VUS, n=2). Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:4
PCDH15: BS2 -
This variant is associated with the following publications: (PMID: 26969326) -
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Usher syndrome type 1F Uncertain:1
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Usher syndrome type 1 Uncertain:1
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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