WNK3
protein-codingWNK lysine deficient protein kinase 3, the group of WNK lysine deficient protein kinases
Gene summary
This gene encodes a protein belonging to the 'with no lysine' family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase-3-dependent pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]
- PRKWNK3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~165.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010667
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010667
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to WNK3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020922.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 22 | 8 | 6 | 36 | ||
| missense | 3 | 284 | 35 | 2 | 324 | |
| nonsense | 3 | 1 | 8 | 12 | ||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 2 | 10 | 12 | |||
| Total | 8 | 2 | 326 | 43 | 8 | 387 |
Highest pathogenic variant AF is 9.114923e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_065973.2 | 23 | MANE Select | |
| Ensembl | ENSP00000346667.2 | 23 | MANE Select | |
| RefSeq | NP_001002838.1 | 22 | Standard | |
| RefSeq | NP_001382095.1 | 22 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Diuretics Pathway, Pharmacodynamics
- Stimuli-sensing channels
- Ion channel transport
- Transport of small molecules
Biological Process
- protein phosphorylation
- positive regulation of sodium ion transport
- negative regulation of sodium ion transport
- positive regulation of peptidyl-threonine phosphorylation
- positive regulation of ion transmembrane transporter activity
Molecular Function
- protein kinase activity
- protein serine/threonine kinase activity
- protein binding
- ATP binding
- chloride channel inhibitor activity
Cellular Component
- cytoplasm
- cytosol
- adherens junction
- bicellular tight junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000354646
- Coding exons
- 23
- Length
- 165820
- Individuals with no LoFs
- 125551
- Homozygous LoFs
- 3
- Heterozygous LoFs
- 4
- Defined
- 125558
- p
- 0.0000279
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.55 | 453 | 634 | 0.715 | 0.0000466 | 11756 |
| Missense (PolyPhen) | 74 | 197.53 | 0.37462 | 3703 | ||
| Synonymous | 1.68 | 195 | 227 | 0.858 | 0.0000167 | 3519 |
| Loss of Function | 6.26 | 5 | 55.1 | 0.0907 | 0.00000421 | 1040 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000043 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000064 | 0.000046 | rare |
| European (Non-Finnish) | 0.000013 | 0.0000088 | rare |
| South Asian | 0.00026 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively (PubMed:16275913, PubMed:16275911, PubMed:16357011). Phosphorylates WNK4. Regulates the phosphorylation of SLC12A1 and SLC12A2. Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway (PubMed:18768590). Inhibits the activity of KCNJ1 by decreasing its expression at the cell membrane in a non-catalytic manner. {ECO:0000269|PubMed:16275911, ECO:0000269|PubMed:16275913, ECO:0000269|PubMed:16357011, ECO:0000269|PubMed:16501604, ECO:0000269|PubMed:17975670, ECO:0000269|PubMed:18768590, ECO:0000269|PubMed:20525693}.;
Recessive Scores
- pRec
- 0.123
Intolerance Scores
- RVIS EVS
- -1.33
- RVIS percentile EVS
- 4.71
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
- Indispensability pred.
- N
- Indispensability score
- 0.0876
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |