rs149208928
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The ENST00000395445.6(PCDH15):āc.4541A>Cā(p.Glu1514Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000904 in 1,611,732 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0053 ( 8 hom., cov: 32)
Exomes š: 0.00045 ( 8 hom. )
Consequence
PCDH15
ENST00000395445.6 missense
ENST00000395445.6 missense
Scores
1
3
10
Clinical Significance
Conservation
PhyloP100: 4.06
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 (MetaRNN=0.0046368837).
BP6
?
Variant 10-53809503-T-G is Benign according to our data. Variant chr10-53809503-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 178678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809503-T-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00527 (802/152300) while in subpopulation AFR AF= 0.0183 (760/41556). AF 95% confidence interval is 0.0172. There are 8 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 8 AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_001384140.1 | c.4671+1053A>C | intron_variant | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000644397.2 | c.4671+1053A>C | intron_variant | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00528 AC: 803AN: 152182Hom.: 8 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00128 AC: 314AN: 246268Hom.: 3 AF XY: 0.00104 AC XY: 139AN XY: 133722
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GnomAD4 exome AF: 0.000449 AC: 655AN: 1459432Hom.: 8 Cov.: 33 AF XY: 0.000394 AC XY: 286AN XY: 725830
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GnomAD4 genome ? AF: 0.00527 AC: 802AN: 152300Hom.: 8 Cov.: 32 AF XY: 0.00500 AC XY: 372AN XY: 74468
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ESP6500AA
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Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 19, 2013 | Glu1521Ala in Exon 37A of PCDH15: This variant is not expected to have clinical significance because it has been identified in 1.9% (60/3136) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs149208928). - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 26, 2017 | - - |
PCDH15-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 04, 2023 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T;T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;N;N;N;N;N;N
PROVEAN
Benign
N;N;N;.;.;.
REVEL
Benign
Sift
Uncertain
D;D;D;.;.;.
Sift4G
Benign
T;T;T;T;T;T
Vest4
MVP
ClinPred
T
GERP RS
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