GeneBe

PKD2

protein-coding

polycystin 2, transient receptor potential cation channel, the group of Transient receptor potential cation channels|EF-hand domain containing

Gene summary

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]

MANE transcript

NM_000297.4

Inheritance

AR, AD

ClinVar variants

P:487U:681B:248

Top phenotype

Polycystic kidney disease 2 with or without polycystic liver disease

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr4:88,007,635-88,077,777

External References & Databases

Ensembl (ENSG00000118762)NCBI Gene (5311)OMIM (173910)HGNC:9009GenCCUniProt (Q13563)AlphaFoldClinVar (PKD2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~70.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

polycystic kidney disease 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013131

Submitter: Ambry Genetics

autosomal dominant polycystic kidney diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: ClinGen

The PKD2 gene has been associated with autosomal dominant polycystic kidney disease in over 15 probands in 6 curated publications. PKD2 was first associated with this disease in humans in 1996 (Mochizuki et al.). Variants in this gene segregate with disease and can occur de novo. The mechanism for disease is known to be loss of function. 53 unique variants (missense, in-frame indel, nonsense, frameshift, large deletion and complex rearrangements) have been classified as Pathogenic in ClinVar, 30 of which are frameshift, nonsense or canonical splice changes. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by ample experimental evidence including expression studies, biochemical function, protein interactions and animal models that recapitulate the human disease. Evidence to support a biallelic PKD2 phenotype in humans has been reviewed, but there is currently insufficient literature available to support an autosomal recessive gene-disease relationship (PMIDs: 22114106, 33168999). In summary, PKD2 is definitively associated with autosomal dominant polycystic kidney disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Working Group on 5/22/2019 (SOP Version 6).

polycystic kidney disease 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013131

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant polycystic kidney diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: Orphanet

polycystic kidney disease 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013131

Submitter: PanelApp Australia

polycystic kidney disease 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013131

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Polycystic kidney disease 2 with or without polycystic liver diseaseAD

Manifestation: Cardiovascular; Gastrointestinal; Renal

Intervention: Cardiovascular; Gastrointestinal; Pharmacogenomic; Renal

Rationale: A number of manifestations can benefit from surveillance and early treatment, including surveillance for cardiovascular findings such as intracranial aneurysms and aortic dilation can allow early detection and treatment; Treatment for hypertension is frequently required (eg, with ACE inhibitors/angiotensin II receptor blockers); A number of agents should be avoided, including nephrotoxic agents, estrogens, smoking and agents that increase renal cysts; Additional considerations related to hepatic and other cyst-related manifestations may be beneficial

Refs: 8650545; 9402976; 9326320; 9773786; 9573526; 11156533; 11752048; 17699192; 17699202; 16707749; 17035604; 19443633; 20301424; 20219616; 21544064; 21551026Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PKD2 variants in ClinVar

27 Conditions Cataloged
Autosomal dominant polycystic kidney diseaseTotal: 801
Polycystic kidney disease 2Total: 699
not providedTotal: 338
PKD2-related disorderTotal: 249
Inborn genetic diseasesTotal: 165
not specifiedTotal: 88
Polycystic kidney diseaseTotal: 82
Cystic renal diseaseTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000297.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
14
clinvar
198
clinvar
5
clinvar
 219
missense
1
clinvar
29
clinvar
650
clinvar
43
clinvar
2
clinvar
 725
nonsense
100
clinvar
23
clinvar
3
clinvar
 126
start loss
2
clinvar
 2
frameshift
185
clinvar
74
clinvar
5
clinvar
 264
splice donor/acceptor (+/-2bp)
37
clinvar
36
clinvar
7
clinvar
 80
Total32316468124171416

Highest pathogenic variant AF is 0.000010373114

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000297.4RefSeqNP_000288.115MANE Select
ENST00000237596.7EnsemblENSP00000237596.215MANE Select
NM_001440544.1RefSeqNP_001427473.114Standard
ENST00000502363.1EnsemblENSP00000425289.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
pkd2Danio rerio

Structure: thoracic duct

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Polycystic Kidney Disease Pathway
  • VxPx cargo-targeting to cilium
  • Cargo trafficking to the periciliary membrane
  • Cilium Assembly
  • Organelle biogenesis and maintenance

Biological Process

  • branching involved in ureteric bud morphogenesis
  • liver development
  • embryonic placenta development
  • heart looping
  • detection of nodal flow

Molecular Function

  • signaling receptor binding
  • voltage-gated ion channel activity
  • voltage-gated calcium channel activity
  • voltage-gated sodium channel activity
  • voltage-gated potassium channel activity

Cellular Component

  • polycystin complex
  • cytoplasm
  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000237596
Coding exons
15
Length
70110
Individuals with no LoFs
125716
Homozygous LoFs
0
Heterozygous LoFs
29
Defined
125745
p
0.000115
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2724494660.9640.00002686327
Missense (PolyPhen)143166.720.857752213
Synonymous-1.912081761.180.00001051891
Loss of Function4.361648.90.3270.00000343509

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish00.0absent
East Asian0.000220.00022rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.0000970.000097rare
South Asian0.000200.00020rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Functions as a cation channel involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (PubMed:18695040). Functions as outward-rectifying K(+) channel, but is also permeable to Ca(2+), and to a much lesser degree also to Na(+) (PubMed:11854751, PubMed:15692563, PubMed:27071085, PubMed:27991905). May contribute to the release of Ca(2+) stores from the endoplasmic reticulum (PubMed:11854751, PubMed:20881056). Together with TRPV4, forms mechano- and thermosensitive channels in cilium (PubMed:18695040). PKD1 and PKD2 may function through a common signaling pathway that is necessary to maintain the normal, differentiated state of renal tubule cells. Acts as a regulator of cilium length, together with PKD1. The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling. The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling. Also involved in left-right axis specification via its role in sensing nodal flow; forms a complex with PKD1L1 in cilia to facilitate flow detection in left-right patterning. Detection of asymmetric nodal flow gives rise to a Ca(2+) signal that is required for normal, asymmetric expression of genes involved in the specification of body left-right laterality (By similarity). {ECO:0000250|UniProtKB:O35245, ECO:0000269|PubMed:11854751, ECO:0000269|PubMed:15692563, ECO:0000269|PubMed:16551655, ECO:0000269|PubMed:18695040, ECO:0000269|PubMed:20881056, ECO:0000269|PubMed:27991905, ECO:0000305}.;
Disease
DISEASE: Polycystic kidney disease 2 with or without polycystic liver disease (PKD2) [MIM:613095]: An autosomal dominant disorder characterized by progressive formation and enlargement of cysts in both kidneys, typically leading to end-stage renal disease in adult life. Cysts also occurs in the liver and other organs. It represents approximately 15% of the cases of autosomal dominant polycystic kidney disease. PKD2 is clinically milder than PKD1 but it has a deleterious impact on overall life expectancy. {ECO:0000269|PubMed:10411676, ECO:0000269|PubMed:10541293, ECO:0000269|PubMed:10835625, ECO:0000269|PubMed:11854751, ECO:0000269|PubMed:11968093, ECO:0000269|PubMed:12707387, ECO:0000269|PubMed:14993477, ECO:0000269|PubMed:15772804, ECO:0000269|PubMed:21115670, ECO:0000269|PubMed:27071085, ECO:0000269|PubMed:9326320}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.314

Intolerance Scores

LoFtool
0.366
RVIS EVS
-0.71
RVIS percentile EVS
14.71

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.821

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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