WNK4

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

Basic information

Region (hg38): 17:42780609-42797066

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.

• not provided (140 variants)
• Pseudohypoaldosteronism type 2B (112 variants)
• Inborn genetic diseases (54 variants)
• not specified (6 variants)
• Pseudohypoaldosteronism type 2A (2 variants)
• WNK4-related condition (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	25	15	47
missense	1		92	22	24	139
nonsense			8			8
start loss						0
frameshift		1	7			8
inframe indel		1			1	2
splice donor/acceptor (+/-2bp)			2			2
splice region			1	1	1	3
non coding			5	7	18	30
Total	1	2	121	54	58

Variants in WNK4

This is a list of pathogenic ClinVar variants found in the WNK4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
17-42780677-C-T		Pseudohypoaldosteronism type 2B	Benign (Jan 12, 2018)
17-42780712-C-T		Pseudohypoaldosteronism type 2B	Uncertain significance (Sep 28, 2022)
17-42780713-G-A			Likely benign (Sep 06, 2022)
17-42780714-G-A		Pseudohypoaldosteronism type 2B • WNK4-related disorder	Benign (Feb 12, 2024)
17-42780715-C-A		Inborn genetic diseases	Uncertain significance (Jun 11, 2021)
17-42780731-C-T			Benign (Dec 02, 2023)
17-42780733-T-G			Uncertain significance (Jul 06, 2022)
17-42780735-A-G			Uncertain significance (Sep 17, 2023)
17-42780736-T-G		Inborn genetic diseases	Uncertain significance (Oct 10, 2023)
17-42780743-G-A			Likely benign (May 01, 2022)
17-42780745-C-T		Pseudohypoaldosteronism type 2B	Benign/Likely benign (Sep 19, 2023)
17-42780762-C-A		WNK4-related disorder	Uncertain significance (Dec 21, 2022)
17-42780762-C-G		Inborn genetic diseases	Uncertain significance (Feb 14, 2023)
17-42780777-C-G		Pseudohypoaldosteronism type 2B	Uncertain significance (Jan 12, 2018)
17-42780780-C-G			Uncertain significance (Sep 12, 2023)
17-42780790-C-A		Pseudohypoaldosteronism type 2B	Benign/Likely benign (Nov 01, 2021)
17-42780797-G-A			Likely benign (Dec 18, 2023)
17-42780801-C-T		Inborn genetic diseases	Uncertain significance (Dec 27, 2022)
17-42780838-C-T		Inborn genetic diseases	Uncertain significance (Dec 02, 2022)
17-42780840-G-C			Likely benign (Oct 29, 2023)
17-42780846-G-A		Inborn genetic diseases	Uncertain significance (May 22, 2023)
17-42780852-C-G		Inborn genetic diseases	Uncertain significance (Dec 08, 2021)
17-42780862-G-A		Pseudohypoaldosteronism type 2B	Uncertain significance (Jan 13, 2018)
17-42780880-G-A			Benign (Oct 15, 2023)
17-42780902-G-A		Pseudohypoaldosteronism type 2B	Likely benign (Feb 11, 2022)

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