KCNJ5

potassium inwardly rectifying channel subfamily J member 5, the group of Potassium inwardly rectifying channel subfamily J

Basic information

Region (hg38): 11:128891356-128921163

Links

ENSG00000120457 ∙ NCBI:3762 ∙ OMIM:600734 ∙ HGNC:6266 ∙ Uniprot:P48544 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Andersen-Tawil syndrome (Supportive), mode of inheritance: AD
• familial hyperaldosteronism type III (Supportive), mode of inheritance: AD
• familial hyperaldosteronism type III (Strong), mode of inheritance: AD
• long QT syndrome 13 (Limited), mode of inheritance: AD
• long QT syndrome (Disputed Evidence), mode of inheritance: AD
• long QT syndrome 13 (Limited), mode of inheritance: AD
• familial hyperaldosteronism type III (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Long QT syndrome 13; Hyperaldosteronism, familial, type III	AD	Cardiovascular; Endocrine	In Long QT syndrome, preventive measures and medical management may be helpful to help decrease morbidity; sudden death in infancy has been reported; In Hyperaldosteronism, familial, hypertension and aldosteronism are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy	Cardiovascular; Endocrine	18505761; 20301308; 20560207; 21311022; 22447138; 22628607; 24574546

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNJ5 gene.

• Familial hyperaldosteronism type III (2 variants)
• Long QT syndrome (2 variants)
• not provided (1 variants)
• Cardiovascular phenotype (1 variants)
• Aldosterone-producing adrenal adenoma, somatic (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNJ5 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			2	90	4	96
missense	2	1	160	5	2	170
nonsense			5	1		6
start loss						0
frameshift			7			7
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region			2	1	1	4
non coding			60	21	25	106
Total	2	1	236	117	31

Variants in KCNJ5

This is a list of pathogenic ClinVar variants found in the KCNJ5 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-128891397-G-GACAC		Familial hyperaldosteronism • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
11-128891425-C-G		Familial hyperaldosteronism type III	Uncertain significance (Feb 02, 2018)
11-128891427-C-G		Familial hyperaldosteronism type III	Uncertain significance (Jan 13, 2018)
11-128891427-CACACACACACACAC-GAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891429-C-G		Familial hyperaldosteronism type III	Conflicting classifications of pathogenicity (May 16, 2021)
11-128891429-CACACACACACAC-GAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891429-CACACACACACAC-GAGAG		Familial hyperaldosteronism • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
11-128891429-CACACACACACAC-GAGAGAG		Familial hyperaldosteronism • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
11-128891429-CACACACACACAC-GAGAGAGAGAGAGAGAGAGAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891431-C-G		Familial hyperaldosteronism type III	Conflicting classifications of pathogenicity (May 12, 2021)
11-128891431-CACACACACAC-G		Familial hyperaldosteronism • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
11-128891431-CACACACACAC-GAG		Familial hyperaldosteronism • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
11-128891431-CACACACACAC-GAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891431-CACACACACAC-GAGAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891431-CACACACACAC-GAGAGAGAGAGAGAG		Familial hyperaldosteronism • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
11-128891433-C-G		Familial hyperaldosteronism type III	Conflicting classifications of pathogenicity (May 12, 2021)
11-128891433-CACACACAC-GAGAG		Familial hyperaldosteronism • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
11-128891435-C-G		Familial hyperaldosteronism type III	Conflicting classifications of pathogenicity (May 12, 2021)
11-128891435-CACACAC-GAGAGAGAGAGAGAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891435-CACACAC-GAGAGAGAGAGAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891435-C-CAGAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891437-C-G		Familial hyperaldosteronism type III • Congenital long QT syndrome	Conflicting classifications of pathogenicity (May 12, 2021)
11-128891437-CACAC-GAGAGAGAGAGAGAGAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891437-CACAC-GAGAGAGAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)
11-128891437-CACAC-GAGAGAGAGAGAG		Congenital long QT syndrome • Familial hyperaldosteronism	Uncertain significance (Jun 14, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCNJ5	protein_coding	protein_coding	ENST00000529694	2	29680

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000336	0.834	125727	0	21	125748	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.33	190	249	0.763	0.0000162	2777
Missense in Polyphen		92	124.85	0.73686		1338
Synonymous	-0.388	104	99.1	1.05	0.00000663	828
Loss of Function	1.23	7	11.5	0.608	6.93e-7	125

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000206	0.000206
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000933	0.0000924
European (Non-Finnish)	0.0000616	0.0000615
Middle Eastern	0.000109	0.000109
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium. {ECO:0000269|PubMed:22315453, ECO:0000269|PubMed:22628607, ECO:0000269|PubMed:24037882, ECO:0000269|PubMed:27099398, ECO:0000269|PubMed:27293068}.
• Disease: DISEASE: Hyperaldosteronism, familial, 3 (HALD3) [MIM:613677]: A form of hyperaldosteronism characterized by hypertension secondary to massive adrenal mineralocorticoid production. HALD3 patients present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. Hypertension and aldosteronism are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension. {ECO:0000269|PubMed:21311022, ECO:0000269|PubMed:22203740, ECO:0000269|PubMed:22275527, ECO:0000269|PubMed:22308486, ECO:0000269|PubMed:22315453, ECO:0000269|PubMed:22628607, ECO:0000269|PubMed:22848660, ECO:0000269|PubMed:24037882, ECO:0000269|PubMed:27099398}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Somatic mutations in KCNJ5 have been found in aldosterone-producing adrenal adenomas and can be responsible for aldosteronism associated with cell autonomous proliferation. APAs are typically solitary, well circumscribed tumors diagnosed between ages 30 and 70. They come to medical attention due to new or worsening hypertension, often with hypokalemia. The precise role of KCNJ5 mutations in APA is under debate. They produce increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation. However, they may not be causative of APA development but may be a consequence of tumorigenesis, playing only a contributory role toward aldosterone overproduction and tumor growth (PubMed:22275527). Somatic mutations in KCNJ5 have not been found in non-aldosterone secreting adrenal adenomas suggesting that they are specifically associated with APA (PubMed:22275527 and PubMed:22848660). {ECO:0000269|PubMed:21311022, ECO:0000269|PubMed:22203740, ECO:0000269|PubMed:22275527, ECO:0000269|PubMed:22848660}.; DISEASE: Note=Mutations in KCNJ5 are involved in the pathogenesis of hypertension without primary aldosteronism but with increased aldosterone response to ACTH stimulation. {ECO:0000269|PubMed:27293068}.
• Pathway: Aldosterone synthesis and secretion - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Retrograde endocannabinoid signaling - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Notch Signaling Pathway;Notch Signaling Pathway;Calcium Regulation in the Cardiac Cell;Neuronal System;Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits;Activation of GABAB receptors;GABA B receptor activation;GABA receptor activation;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Activation of G protein gated Potassium channels;G protein gated Potassium channels;Inwardly rectifying K+ channels;Potassium Channels (Consensus)

Recessive Scores

• pRec: 0.167

Intolerance Scores

• loftool: 0.101
• rvis_EVS: -0.53
• rvis_percentile_EVS: 20.7

Haploinsufficiency Scores

• pHI: 0.146
• hipred: Y
• hipred_score: 0.651
• ghis: 0.585

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.372

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kcnj5
• 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: potassium ion transport;regulation of ion transmembrane transport;regulation of heart rate by cardiac conduction;membrane repolarization during atrial cardiac muscle cell action potential;membrane repolarization during ventricular cardiac muscle cell action potential;ventricular cardiac muscle cell membrane repolarization;potassium ion import across plasma membrane
• Cellular component: plasma membrane;voltage-gated potassium channel complex;external side of plasma membrane;T-tubule
• Molecular function: inward rectifier potassium channel activity;protein binding;G-protein activated inward rectifier potassium channel activity;voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization;voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization