rs753690225
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_033056.4(PCDH15):c.5364_5373del(p.Pro1789LeufsTer52) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000127 in 1,579,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
PCDH15
NM_033056.4 frameshift
NM_033056.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.66
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. There are 6 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 | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.5364_5373del | p.Pro1789LeufsTer52 | frameshift_variant | 33/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.4368-2132_4368-2123del | intron_variant | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.5364_5373del | p.Pro1789LeufsTer52 | frameshift_variant | 33/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.4368-2132_4368-2123del | intron_variant | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000660 AC: 1AN: 151620Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000314 AC: 6AN: 191288Hom.: 0 AF XY: 0.0000486 AC XY: 5AN XY: 102816
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GnomAD4 exome AF: 0.0000133 AC: 19AN: 1427796Hom.: 0 AF XY: 0.0000113 AC XY: 8AN XY: 707588
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GnomAD4 genome ? AF: 0.00000660 AC: 1AN: 151620Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74060
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 16, 2022 | - - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | - | - - |
Usher syndrome type 1F Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2017 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at