WNK4

WNK lysine deficient protein kinase 4, the group of WNK lysine deficient protein kinases

Basic information

Region (hg38): 17:42780610-42797066

Previous symbols: [ "PRKWNK4" ]

Links

ENSG00000126562

∙ NCBI:65266 ∙ OMIM:601844 ∙ HGNC:14544 ∙ Uniprot:Q96J92 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

pseudohypoaldosteronism type 2B (Strong), mode of inheritance: AD
pseudohypoaldosteronism type 2B (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pseudohypoaldosteronism, type IIB	AD	Renal	Treatment (eg, correction of physiologic abnormalities by thiazide diuretics) can be effective, and measures towards optimizing blood pressure can decrease morbidity and mortality related to potential sequale of hypertension	Renal	718349; 718348; 504550; 6103235; 9171836; 11498583; 19016006; 22266938; 22073419

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WNK4 gene.

Pseudohypoaldosteronism_type_2B (271 variants)
not_provided (250 variants)
Inborn_genetic_diseases (175 variants)
not_specified (22 variants)
WNK4-related_disorder (18 variants)
Pseudohypoaldosteronism_type_2A (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WNK4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000032387.5. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			15 clinvar	52 clinvar	18 clinvar	85
missense	4 clinvar		317 clinvar	56 clinvar	12 clinvar	389
nonsense			11 clinvar	1 clinvar		12
start loss						0
frameshift		1 clinvar	21 clinvar	1 clinvar		23
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	4	1	369	110	30

Highest pathogenic variant AF is 0.00000205215

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WNK4	protein_coding	protein_coding	ENST00000246914	18	16259

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.88e-25	0.0199	125485	0	263	125748	0.00105

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.814	665	727	0.915	0.0000451	7898
Missense in Polyphen		104	99.883	1.0412		1073
Synonymous	0.690	292	307	0.950	0.0000195	2739
Loss of Function	1.26	43	52.9	0.813	0.00000303	570

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00143	0.00143
Ashkenazi Jewish	0.000206	0.000198
East Asian	0.00246	0.00245
Finnish	0.000237	0.000231
European (Non-Finnish)	0.00130	0.00129
Middle Eastern	0.00246	0.00245
South Asian	0.000653	0.000653
Other	0.000992	0.000978

dbNSFP

Source: dbNSFP

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. Activates SCNN1A, SCNN1B, SCNN1D, SGK1, TRPV5 and TRPV6. Regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation which appears to prevent membrane trafficking of SLC12A3. Also inhibits the renal K(+) channel, KCNJ1, via a kinase-independent mechanism by which it induces clearance of the protein from the cell surface by clathrin-dependent endocytosis. WNK4 appears to act as a molecular switch that can vary the balance between NaCl reabsorption and K(+) secretion to maintain integrated homeostasis. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity). {ECO:0000250|UniProtKB:Q80UE6, ECO:0000269|PubMed:20525693}.;
Disease: DISEASE: Pseudohypoaldosteronism 2B (PHA2B) [MIM:614491]: An autosomal dominant disorder characterized by hypertension, hyperkalemia, hyperchloremia, mild hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. {ECO:0000269|PubMed:11498583, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Diuretics Pathway, Pharmacodynamics;Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Recessive Scores

pRec: 0.246

Intolerance Scores

loftool: 0.889
rvis_EVS: 0.37
rvis_percentile_EVS: 74.74

Haploinsufficiency Scores

pHI: 0.117
hipred: N
hipred_score: 0.419
ghis: 0.390

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.814

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

Gene name: Wnk4
Phenotype: homeostasis/metabolism phenotype; renal/urinary system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan);

Gene ontology

Biological process: protein phosphorylation;ion transport;chloride transport;protein localization;negative regulation of sodium ion transport;positive regulation of ion transmembrane transporter activity;intracellular signal transduction;regulation of cellular process;ion homeostasis;renal sodium ion absorption;distal tubule morphogenesis;negative regulation of pancreatic juice secretion;positive regulation of potassium ion import across plasma membrane;positive regulation of sodium ion transmembrane transporter activity
Cellular component: cytoplasm;cytosol;bicellular tight junction;membrane
Molecular function: protein serine/threonine kinase activity;protein binding;ATP binding;chloride channel inhibitor activity;potassium channel inhibitor activity