chr10-53857257-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_033056.4(PCDH15):c.3724G>A(p.Val1242Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,610,120 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1242V) has been classified as Likely benign.
Frequency
Consequence
NM_033056.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.3724G>A | p.Val1242Met | missense_variant | 28/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.3724G>A | p.Val1242Met | missense_variant | 28/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.3724G>A | p.Val1242Met | missense_variant | 28/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.3724G>A | p.Val1242Met | missense_variant | 28/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.000244 AC: 37AN: 151800Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.000375 AC: 94AN: 250950Hom.: 0 AF XY: 0.000317 AC XY: 43AN XY: 135692
GnomAD4 exome AF: 0.000132 AC: 192AN: 1458202Hom.: 1 Cov.: 29 AF XY: 0.000113 AC XY: 82AN XY: 725650
GnomAD4 genome ? AF: 0.000250 AC: 38AN: 151918Hom.: 1 Cov.: 31 AF XY: 0.000202 AC XY: 15AN XY: 74260
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 01, 2016 | p.Val1242Met in exon 28 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.5% (47/8638) of East Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs201137087). - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 09, 2022 | Variant summary: PCDH15 c.3724G>A (p.Val1242Met) results in a conservative amino acid change located in the Cadherin-like domain of 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 0.00037 in 250950 control chromosomes, predominantly at a frequency of 0.0046 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.45 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 East Asian origin. c.3724G>A has been reported in the literature in individuals affected with Usher Syndrome Type 1, hereditary hearing loss and inherited retinal dystrophies (Yoshimura_2014, Chen_2016, Liu_2020). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three labs classified as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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). 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. - |
Usher syndrome type 1F Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 26, 2019 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at