rs1554815895
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_001142769.3(PCDH15):c.4542dupA(p.Pro1515fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,606,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PCDH15
NM_001142769.3 frameshift
NM_001142769.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.248
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 Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.155 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCDH15 | NM_001384140.1 | c.4671+1033dupA | intron_variant | ENST00000644397.2 | NP_001371069.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000644397.2 | c.4671+1033dupA | intron_variant | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000206 AC: 3AN: 1454424Hom.: 0 Cov.: 33 AF XY: 0.00000415 AC XY: 3AN XY: 723128
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74264
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2017 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro1515fs variant in PCDH15 (NM_001142769.1) has been reported in 3 individuals with hear ing loss: two were homozygous, and one was compound heterozygous with another pa thogenic variant in PCDH15 and segregated in the compound heterozygous state wit h disease in another affected sibling (Pepermans 2014, LMM data). This variant has not been reported in large population studies. This variant is predicted to cause a frameshift in one of the PCDH15 splicing isoforms, which alters the prot ein's amino acid sequence beginning at position 1515 and leads to a premature te rmination codon 4 amino acids downstream. This termination codon occurs within t he last exon of the isoform and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. It is unclear whether the PCDH15 isofo rm is required for hearing and whether the predicted truncated protein is functi onal. In summary, while there is some suspicion for a pathogenic role, the clini cal significance of this variant is uncertain due to the uncertain functional im pact. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at