rs58461416
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_033056.4(PCDH15):c.5286T>A(p.Pro1762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,592,162 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0030 ( 20 hom., cov: 32)
Exomes 𝑓: 0.0020 ( 90 hom. )
Consequence
PCDH15
NM_033056.4 synonymous
NM_033056.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.344
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 -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 10-53822440-A-T is Benign according to our data. Variant chr10-53822440-A-T is described in ClinVar as [Benign]. Clinvar id is 46492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.344 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.5286T>A | p.Pro1762= | synonymous_variant | 33/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.4368-2210T>A | intron_variant | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.5286T>A | p.Pro1762= | synonymous_variant | 33/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.4368-2210T>A | intron_variant | NM_001384140.1 |
Frequencies
GnomAD3 genomes AF: 0.00298 AC: 450AN: 150818Hom.: 20 Cov.: 32
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GnomAD3 exomes AF: 0.00655 AC: 1400AN: 213664Hom.: 60 AF XY: 0.00602 AC XY: 699AN XY: 116058
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GnomAD4 exome AF: 0.00199 AC: 2868AN: 1441226Hom.: 90 Cov.: 32 AF XY: 0.00187 AC XY: 1339AN XY: 715488
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GnomAD4 genome AF: 0.00298 AC: 450AN: 150936Hom.: 20 Cov.: 32 AF XY: 0.00320 AC XY: 236AN XY: 73808
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ClinVar
Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 25, 2010 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 13, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 28, 2022 | - - |
Usher syndrome type 1F Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Usher syndrome type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at