rs1232369409
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000297.4(PKD2):c.514del(p.Asp172ThrfsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PKD2
NM_000297.4 frameshift
NM_000297.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.32
Genes affected
PKD2 (HGNC:9009): (polycystin 2, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein is a multi-pass membrane protein that functions as a calcium permeable cation channel, and is involved in calcium transport and calcium signaling in renal epithelial cells. This protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis. Mutations in this gene are associated with autosomal dominant polycystic kidney disease type 2. [provided by RefSeq, Mar 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-88008243-CG-C is Pathogenic according to our data. Variant chr4-88008243-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 448037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD2 | NM_000297.4 | c.514del | p.Asp172ThrfsTer61 | frameshift_variant | 1/15 | ENST00000237596.7 | |
PKD2 | XM_011532028.3 | c.514del | p.Asp172ThrfsTer61 | frameshift_variant | 1/14 | ||
PKD2 | NR_156488.2 | n.613del | non_coding_transcript_exon_variant | 1/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD2 | ENST00000237596.7 | c.514del | p.Asp172ThrfsTer61 | frameshift_variant | 1/15 | 1 | NM_000297.4 | P1 | |
ENST00000662475.1 | n.112+122del | intron_variant, non_coding_transcript_variant | |||||||
PKD2 | ENST00000506727.1 | n.16del | non_coding_transcript_exon_variant | 1/4 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152026Hom.: 0 Cov.: 32
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1301516Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 639866
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 20, 2016 | - - |
Autosomal dominant polycystic kidney disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2017 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). This variant has not been reported in the literature in individuals with a PKD2-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Asp172Thrfs*61) in the PKD2 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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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