rs1302726543
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000297.4(PKD2):c.637C>T(p.Arg213*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,606,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PKD2
NM_000297.4 stop_gained
NM_000297.4 stop_gained
Scores
4
1
2
Clinical Significance
Conservation
PhyloP100: 2.42
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 4-88019499-C-T is Pathogenic according to our data. Variant chr4-88019499-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 543947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88019499-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKD2 | NM_000297.4 | c.637C>T | p.Arg213* | stop_gained | Exon 2 of 15 | ENST00000237596.7 | NP_000288.1 | |
| PKD2 | XM_011532028.3 | c.637C>T | p.Arg213* | stop_gained | Exon 2 of 14 | XP_011530330.1 | ||
| PKD2 | NR_156488.2 | n.736C>T | non_coding_transcript_exon_variant | Exon 2 of 14 | ||||
| PKD2 | XM_011532029.2 | c.-140C>T | upstream_gene_variant | XP_011530331.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 151966Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1454698Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 724180
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GnomAD4 genome 0.00000658 AC: 1AN: 151966Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74228
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 30, 2019 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2024 | Nonsense 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); This variant is associated with the following publications: (PMID: 25333066, 27499327, 31589614, 36964972, 35372954, 22863349, 33437033, 35005812, 30586318) - |
| Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Polycystic kidney disease 2 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The c.637C>T(p.Arg213Ter) stop gained variant in PKD2 gene has been reported in several individuals with a personal and/or family history of autosomal dominant polycystic kidney disease (Robinson et al., 2012; Trujillano et al., 2014). This variant is reported with the allele frequency (0.003%) in the gnomad and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.637C>T in PKD2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in PKD2 are known to be pathogenic (Robinson et al., 2012). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 21, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 05, 2019 | The PKD2 c.637C>T; p.Arg213Ter variant (rs1302726543) is reported in the literature in multiple individuals affected with autosomal dominant polycystic kidney disease (Carrera 2016, Robinson 2012, Trujillano 2014). This variant is found on a single chromosome (1/31368 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 543947). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Carrera P et al. Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Sci Rep. 2016 Aug 8;6:30850. Robinson C et al. Clinical utility of PKD2 mutation testing in a polycystic kidney disease cohort attending a specialist nephrology out-patient clinic. BMC Nephrol. 2012 Aug 3;13:79. Trujillano D et al. Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing. Mol Genet Genomic Med. 2014 Sep;2(5):412-21. - |
Polycystic kidney disease Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD2 p.Arg213* variant was identified in 9 of 1642 proband chromosomes (frequency: 0.005) from individuals or families with ADPKD (Carrera 2016, Robinson 2012, Trujillano 2014). The variant was also identified in the ClinVar database (classified as pathogenic by Invitae and one clinical laboratory), COSMIC (1x in breast tissue), and in LOVD 3.0(2x). The variant was not identified in dbSNP, ADPKD Mutation Database, ADPKD-LOVD or COGR databases. The variant was identified in control databases in 1 of 30942 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the African population in 1 of 8718 chromosomes (freq: 0.0001), but not in the European, “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg213* variant leads to a premature stop codon at position 213, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD2 gene are an established mechanism of disease in autosomal dominant polycystic kidney disease and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Autosomal dominant polycystic kidney disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 06, 2022 | This sequence change creates a premature translational stop signal (p.Arg213*) in the PKD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with a personal and/or family history of autosomal dominant polycystic kidney disease (PMID: 22863349, 25333066, 27499327). ClinVar contains an entry for this variant (Variation ID: 543947). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
D
Vest4
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