WNK1

WNK lysine deficient protein kinase 1, the group of WNK lysine deficient protein kinases|Protein phosphatase 1 regulatory subunits|Minor histocompatibility antigens

Basic information

Region (hg38): 12:752579-911452

Previous symbols: [ "PRKWNK1", "HSN2" ]

Links

ENSG00000060237 ∙ NCBI:65125 ∙ OMIM:605232 ∙ HGNC:14540 ∙ Uniprot:Q9H4A3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary sensory and autonomic neuropathy type 2 (Supportive), mode of inheritance: AR
• neuropathy, hereditary sensory and autonomic, type 2A (Strong), mode of inheritance: AR
• pseudohypoaldosteronism type 2C (Moderate), mode of inheritance: AD
• neuropathy, hereditary sensory and autonomic, type 2A (Strong), mode of inheritance: AR
• pseudohypoaldosteronism type 2C (Strong), mode of inheritance: AD
• neuropathy, hereditary sensory and autonomic, type 2A (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pseudohypoaldosteronism, type IIC; Neuropathy, hereditary sensory and autonomic, type IIA	AD/AR	Neurologic; 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; In Neuropathy, hereditary sensory and autonomic, type IIl, reduced pain sensation may result in injury, as well as result in ulceration/infection, and precautions may be beneficial	Neurologic; Renal	20323803; 10869238; 11498583; 15060842; 5455397; 15911806; 16946995; 16636245; 16534117; 18521183; 22080857; 22266938; 21768522; 22073419; 22910560; 22934535

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WNK1 gene.

• Pseudohypoaldosteronism type 2C;Neuropathy, hereditary sensory and autonomic, type 2A (14 variants)
• Neuropathy, hereditary sensory and autonomic, type 2A;Pseudohypoaldosteronism type 2C (13 variants)
• Neuropathy, hereditary sensory and autonomic, type 2A (8 variants)
• Inborn genetic diseases (6 variants)
• not provided (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WNK1 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			17	401	13	431
missense		1	865	42	9	917
nonsense	15	1	6	1		23
start loss						0
frameshift	18	1	19	1	2	41
inframe indel			18	2		20
splice donor/acceptor (+/-2bp)		6	1			7
splice region			22	29	2	53
non coding		1	58	139	93	291
Total	33	10	984	586	117

Highest pathogenic variant AF is 0.0000197

Variants in WNK1

This is a list of pathogenic ClinVar variants found in the WNK1 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-752928-C-T		Pseudohypoaldosteronism type 2C	Uncertain significance (Jan 13, 2018)
12-752968-C-G		Pseudohypoaldosteronism type 2C	Benign (Jan 13, 2018)
12-753052-C-T		Pseudohypoaldosteronism type 2C	Likely benign (Jan 12, 2018)
12-753114-G-A		Pseudohypoaldosteronism type 2C	Benign (Jul 06, 2018)
12-753193-G-C		Pseudohypoaldosteronism type 2C	Uncertain significance (Jan 12, 2018)
12-753198-G-T		Pseudohypoaldosteronism type 2C	Uncertain significance (Jan 12, 2018)
12-753212-G-GC		Pseudohypoaldosteronism type 2A • Hereditary sensory and autonomic neuropathy type 2	Uncertain significance (Jun 14, 2016)
12-753238-C-G		Pseudohypoaldosteronism type 2C	Benign/Likely benign (Jun 26, 2018)
12-753258-G-T		Hereditary sensory and autonomic neuropathy type 2 • Pseudohypoaldosteronism type 2A	Uncertain significance (Jun 14, 2016)
12-753275-G-A		Pseudohypoaldosteronism type 2C	Uncertain significance (Jan 12, 2018)
12-753303-C-A		Pseudohypoaldosteronism type 2C	Uncertain significance (Jan 12, 2018)
12-753306-G-T		Pseudohypoaldosteronism type 2C	Uncertain significance (Jan 13, 2018)
12-753313-A-G		Pseudohypoaldosteronism type 2C	Uncertain significance (Jan 13, 2018)
12-753332-T-C		Pseudohypoaldosteronism type 2C	Uncertain significance (Jan 13, 2018)
12-753353-G-T		Pseudohypoaldosteronism type 2C	Benign (Jan 13, 2018)
12-753363-C-G		Pseudohypoaldosteronism type 2C	Benign (Jan 13, 2018)
12-753407-C-T		Pseudohypoaldosteronism type 2C	Benign (Jan 12, 2018)
12-753444-C-T		Pseudohypoaldosteronism type 2C	Benign (Jan 13, 2018)
12-753475-T-G		Pseudohypoaldosteronism type 2C • not specified	Benign (Jun 19, 2018)
12-753495-G-A		Pseudohypoaldosteronism type 2C	Benign (Jan 13, 2018)
12-753532-C-T		Pseudohypoaldosteronism type 2C	Benign (Jan 22, 2018)
12-753541-C-G		Pseudohypoaldosteronism type 2C	Benign/Likely benign (Aug 14, 2018)
12-753543-C-T		Pseudohypoaldosteronism type 2C	Benign (Jan 13, 2018)
12-753571-T-G		Neuropathy, hereditary sensory and autonomic, type 2A;Pseudohypoaldosteronism type 2C	Likely benign (Dec 18, 2023)
12-753571-T-TGGC		Pseudohypoaldosteronism type 2C;Neuropathy, hereditary sensory and autonomic, type 2A	Uncertain significance (Oct 25, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WNK1	protein_coding	protein_coding	ENST00000315939	28	158860

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.22e-12	125716	0	32	125748	0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.16	1043	1.26e+3	0.828	0.0000657	15240
Missense in Polyphen		238	314.53	0.75667		3966
Synonymous	-0.881	500	476	1.05	0.0000258	5145
Loss of Function	8.82	7	104	0.0672	0.00000640	1130

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000391	0.000391
Ashkenazi Jewish	0.00109	0.00109
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000440	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.000196	0.000196
Other	0.000163	0.000163

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 and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide- sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4, SLC26A6 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity). {ECO:0000250|UniProtKB:P83741, ECO:0000250|UniProtKB:Q9JIH7, ECO:0000269|PubMed:10660600, ECO:0000269|PubMed:15060842}.
• Disease: DISEASE: Pseudohypoaldosteronism 2C (PHA2C) [MIM:614492]: An autosomal dominant disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, mild hyperchloremic metabolic acidosis in some cases, and correction of physiologic abnormalities by thiazide diuretics. {ECO:0000269|PubMed:11498583}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neuropathy, hereditary sensory and autonomic, 2A (HSAN2A) [MIM:201300]: A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN2A is an autosomal recessive disorder characterized by impairment of pain, temperature and touch sensation, onset of symptoms in infancy or early childhood, occurrence of distal extremity pathologies (paronychia, whitlows, ulcers, and Charcot joints), frequent amputations, sensory loss that affects all modalities of sensation (lower and upper limbs and perhaps the trunk as well), absence or diminution of tendon reflexes (usually in all limbs), minimal autonomic dysfunction, absence of sensory nerve action potentials, and virtual absence of myelinated fibers with decreased numbers of unmyelinated fibers in sural nerves. {ECO:0000269|PubMed:15060842, ECO:0000269|PubMed:15911806, ECO:0000269|PubMed:18521183}. 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: 0.210

Intolerance Scores

• loftool: 0.540
• rvis_EVS: -1.07
• rvis_percentile_EVS: 7.35

Haploinsufficiency Scores

• pHI: 0.259
• hipred: Y
• hipred_score: 0.745
• ghis: 0.553

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.968

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Wnk1
• Phenotype: homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype; renal/urinary system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); 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); hematopoietic system phenotype; embryo phenotype

Zebrafish Information Network

• Gene name: wnk1a
• Affected structure: dorsal longitudinal anastomotic vessel
• Phenotype tag: abnormal
• Phenotype quality: hypoplastic

Gene ontology

• Biological process: regulation of sodium ion transport;positive regulation of systemic arterial blood pressure;protein phosphorylation;ion transport;negative regulation of sodium ion transport;positive regulation of T cell chemotaxis;negative regulation of phosphatase activity;peptidyl-serine phosphorylation;peptidyl-threonine phosphorylation;signal transduction by trans-phosphorylation;activation of protein kinase activity;positive regulation of ion transmembrane transporter activity;negative regulation of cell-cell adhesion mediated by integrin;negative regulation of heterotypic cell-cell adhesion;negative regulation of GTPase activity;intracellular signal transduction;chemokine (C-C motif) ligand 21 signaling pathway;protein autophosphorylation;neuron development;regulation of cellular process;ion homeostasis;T cell receptor signaling pathway;cellular response to calcium ion;negative regulation of protein serine/threonine kinase activity;negative regulation of pancreatic juice secretion;positive regulation of canonical Wnt signaling pathway;lymphocyte migration into lymph node;negative regulation of leukocyte cell-cell adhesion;positive regulation of potassium ion import across plasma membrane;cellular response to chemokine;positive regulation of sodium ion transmembrane transporter activity
• Cellular component: cytoplasm;cytosol;membrane
• Molecular function: magnesium ion binding;protein kinase activity;protein serine/threonine kinase activity;protein binding;ATP binding;chloride channel inhibitor activity;potassium channel inhibitor activity;protein kinase binding;phosphatase binding;protein serine/threonine kinase inhibitor activity;protein kinase activator activity