rs149867749
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_033056.4(PCDH15):c.3983+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,613,324 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0047 ( 7 hom., cov: 32)
Exomes 𝑓: 0.0063 ( 46 hom. )
Consequence
PCDH15
NM_033056.4 intron
NM_033056.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.459
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
Variant 10-53840308-A-G is Benign according to our data. Variant chr10-53840308-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53840308-A-G is described in Lovd as [Likely_benign]. Variant chr10-53840308-A-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00471 (718/152350) while in subpopulation NFE AF= 0.00779 (530/68032). AF 95% confidence interval is 0.00724. There are 7 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 7 AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_001384140.1 | c.3983+12T>C | intron_variant | ENST00000644397.2 | |||
PCDH15 | NM_033056.4 | c.3983+12T>C | intron_variant | ENST00000320301.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.3983+12T>C | intron_variant | 1 | NM_033056.4 | ||||
PCDH15 | ENST00000644397.2 | c.3983+12T>C | intron_variant | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00473 AC: 720AN: 152232Hom.: 7 Cov.: 32
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GnomAD3 exomes AF: 0.00499 AC: 1254AN: 251440Hom.: 8 AF XY: 0.00514 AC XY: 699AN XY: 135888
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GnomAD4 exome AF: 0.00633 AC: 9251AN: 1460974Hom.: 46 Cov.: 31 AF XY: 0.00627 AC XY: 4554AN XY: 726880
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GnomAD4 genome ? AF: 0.00471 AC: 718AN: 152350Hom.: 7 Cov.: 32 AF XY: 0.00462 AC XY: 344AN XY: 74504
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2013 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | 3983+12T>C in Intron 29 of PCDH15: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 0.7% (46/7020) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs149867749). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2018 | Variant summary: PCDH15 c.3983+12T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.0052 in 277196 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency 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 benign. c.3983+12T>C has been reported in the literature in individuals affected with Usher Syndrome Type 1F. These report(s) 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. However, two other clinical diagnostic laboratories classified this variant as benign before 2014. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 08, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 21, 2022 | - - |
Usher syndrome type 1 Benign:1
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
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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