rs1491209806
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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.4907_4908delAA(p.Lys1636fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,986 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 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
PCDH15
NM_033056.4 frameshift
NM_033056.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.485
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 0.164 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_033056.4 | c.4907_4908delAA | p.Lys1636fs | frameshift_variant | 33/33 | ENST00000320301.11 | NP_149045.3 | |
PCDH15 | NM_001384140.1 | c.4368-2589_4368-2588delAA | intron_variant | ENST00000644397.2 | NP_001371069.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.4907_4908delAA | p.Lys1636fs | frameshift_variant | 33/33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.4368-2589_4368-2588delAA | intron_variant | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251448Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135896
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GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461830Hom.: 0 AF XY: 0.0000385 AC XY: 28AN XY: 727218
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74344
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Usher syndrome type 1F Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 12, 2017 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2022 | Frameshift variant predicted to result in protein truncation, as the last 320 amino acids are replaced with 6 different amino acids, and other loss-of-function variants have been reported downstream in HGMD.; Has not been previously published as pathogenic or benign to our knowledge - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | - - |
Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 02, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 10, 2022 | Variant summary: PCDH15 c.4907_4908delAA (p.Lys1636ArgfsX7) located in the last exon of the gene results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Truncating variants in the last exon of PCDH15 have uncertain impact on protein function. The variant allele was found at a frequency of 4.8e-05 in 251448 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (4.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.4907_4908delAA has been reported in the literature in one individual in a carrier screening (Perreault_2014). This report does 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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