rs61735479
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2
The NM_033056.4(PCDH15):c.1362C>T(p.Val454=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,613,658 control chromosomes in the GnomAD database, including 4 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
Genomes: 𝑓 0.0025 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 2 hom. )
Consequence
PCDH15
NM_033056.4 synonymous
NM_033056.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0470
Genes affected
PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
?
Variant 10-54185212-G-A is Benign according to our data. Variant chr10-54185212-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46443.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}. Variant chr10-54185212-G-A is described in Lovd as [Likely_benign]. Variant chr10-54185212-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.047 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00247 (376/152240) while in subpopulation AFR AF= 0.00789 (328/41562). AF 95% confidence interval is 0.00719. There are 2 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 2 AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.1362C>T | p.Val454= | synonymous_variant | 12/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.1362C>T | p.Val454= | synonymous_variant | 12/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.1362C>T | p.Val454= | synonymous_variant | 12/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.1362C>T | p.Val454= | synonymous_variant | 12/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00247 AC: 375AN: 152122Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000744 AC: 187AN: 251360Hom.: 1 AF XY: 0.000626 AC XY: 85AN XY: 135852
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GnomAD4 exome AF: 0.000389 AC: 568AN: 1461418Hom.: 2 Cov.: 31 AF XY: 0.000373 AC XY: 271AN XY: 727022
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GnomAD4 genome ? AF: 0.00247 AC: 376AN: 152240Hom.: 2 Cov.: 32 AF XY: 0.00258 AC XY: 192AN XY: 74440
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 14, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 22, 2012 | Val454Val in exon 12 of PCDH15: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in .014% (1/7020) of Europe an American chromosomes and 0.96% (36/3738) of African American chromosomes in a broad population by the NHLBI Exome sequencing project (http://evs.gs.washingto n.edu/EVS/ ; dbSNP rs61735479). - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 12, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Usher syndrome type 1F Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 25, 2019 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at