KCNJ2
protein-codingpotassium inwardly rectifying channel subfamily J member 2, the group of Potassium inwardly rectifying channel subfamily J
Gene summary
Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008222
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013513
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0018054
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008222
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012314
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: ClinGen
KCNJ2 encodes the alpha subunit of Ik1, the inward rectifier cardiac potassium channel. Pathogenic variants in KCNJ2 are the cause of Andersen-Tawil Syndrome (ATS), a multisystem disorder whose manifestations include dysmorphic features and periodic paralysis. Although patients with ATS are at risk of developing ventricular arrhythmias, these are not typically torsades de pointes, the hallmark of LQTS. Furthermore, ECGs of patients with ATS demonstrate QT-U prolongation and not QT prolongation. Accordingly, the Expert Panel classified the level of evidence for this association as limited. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
Inheritance Pattern: AD
Disease ID:MONDO:0012314
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0000453
Submitter: ClinGen
KCNJ2 encodes the alpha subunit of Ik1, the inward rectifier cardiac potassium channel. Genetic variants in KCNJ2 have been identified in 6 patients from 5 families with unique variants, including at least 2 probands with a de-novo variant. Experimental evidence demonstrated these variants lead to gain-of-function of the late repolarizing, KCNJ2-encoded Ik1 current in the heart, and abbreviation of the action potential duration (PMID 15761194). These data were considered sufficient for classifying the gene-disease relationship of KCNJ2 as ‘Moderate’ but, in the absence of segregation or case-control data, the genetic evidence was not abundant enough for a stronger classification.
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: ClinGen
KCNJ2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). Variants in KCNJ2 are associated with Andersen-Tawil syndrome (ATS), a condition associated with dysmorphic features, periodic paralysis and prominent U waves on ECG. It has been classified as a definitive gene for ATS by the LQTS Gene Curation Expert Panel. As the ECG abnormalities in patients with KCNJ2 variants can be interpreted as prolonged QT intervals, it was also curated for isolated LQTS and found to have limited evidence. KCNJ2 variants have also been implicated in CPVT (referred to as CPVT3 in early reports). However, as in the case with isolated LQTS, it is unclear if these reports actually represent atypical presentations of ATS without extra-cardiac features. A number of reports describe patients with KCNJ2 variants presenting with CPVT-like arrhythmogenic symptoms and without any extra-cardiac features (Tester et al, 2006, PMID:16818210; Kimura et al, 2012, PMID:22589293; Kalscheur et al, 2014, PMID:24561538), supported by functional studies demonstrating effects of the variants on IK1 current in cellular assays (Vega et al, 2009, PMID:19843922; Kimura et al, 2012, PMID:22589293; Kalscheur et al, 2014, PMID:24561538). As a consequence, KCNJ2 scored with limited evidence for involvement in CPVT based on these reports. However, none of these patients presented unequivocally with a classical CPVT phenotype and demonstrated features such as subtle ECG U wave abnormalities and bidirectional VT at rest which may be suggestive of atypical and cardiac-specific ATS rather than a true CPVT diagnosis. The expert panel therefore agreed to classify KCNJ2 as Disputed for CPVT. As patients with pathogenic KCNJ2 variants may present with a phenotype that can resemble typical features of CPVT, it may be beneficial to include this gene in extended arrhythmia genetic testing panels for patients with a CPVT-like phenotype if no causative variants are found when sequencing validated CPVT genes. However, any detected variants should be interpreted in the context of the known genotype-phenotype relationships for KCNJ2, in particular by investigating for subtle phenotypic features associated with ATS. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0000453
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0005453
Submitter: ClinGen
No evidence for a causal role for *KCNJ2* in congenital heart disease has been reported. Although this gene is associated with conduction defects, no reports have directly implicated the gene for structural CHDs in humans. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date October 15th, 2024 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0008222
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012314
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008222
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008222
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal
Intervention: Cardiovascular
Rationale: Depending on the cardiac phenotype, specific medical intervention to prevent morbidity and mortality related to arrhythmias can be beneficial; Surveillance for cardiac events is indicated
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KCNJ2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000891.3. 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 | 169 | 1 | 170 | |||
| missense | 29 | 35 | 278 | 14 | 2 | 358 |
| nonsense | 5 | 2 | 7 | 14 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 4 | 2 | 6 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 39 | 37 | 288 | 183 | 3 | 550 |
Highest pathogenic variant AF is 0.000006571079
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000882.1 | 1 | MANE Select | |
| Ensembl | ENSP00000243457.2 | 1 | MANE Select | |
| Ensembl | ENSP00000441848.1 | 1 | Standard | |
| Ensembl | ENSP00000524950.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Oxytocin signaling pathway - Homo sapiens (human)
- Gastric acid secretion - Homo sapiens (human)
- Renin secretion - Homo sapiens (human)
- Cholinergic synapse - Homo sapiens (human)
- Antiarrhythmic Pathway, Pharmacodynamics
Biological Process
- potassium ion transport
- regulation of skeletal muscle contraction via regulation of action potential
- magnesium ion transport
- cellular potassium ion homeostasis
- protein homotetramerization
Molecular Function
- inward rectifier potassium channel activity
- phosphatidylinositol-4,5-bisphosphate binding
- G-protein activated inward rectifier potassium channel activity
- identical protein binding
- voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization
Cellular Component
- smooth endoplasmic reticulum
- rough endoplasmic reticulum
- Golgi apparatus
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000243457
- Coding exons
- 1
- Length
- 11376
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125735
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.75 | 121 | 241 | 0.502 | 0.0000153 | 2845 |
| Missense (PolyPhen) | 24 | 119.1 | 0.2015 | 1390 | ||
| Synonymous | -0.945 | 104 | 92.4 | 1.13 | 0.00000640 | 830 |
| Loss of Function | 2.51 | 3 | 12.6 | 0.238 | 8.87e-7 | 142 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. 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 extracellular barium or cesium.;
- Disease
- DISEASE: Long QT syndrome 7 (LQT7) [MIM:170390]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. Long QT syndrome type 7 manifests itself as a clinical triad consisting of potassium-sensitive periodic paralysis, ventricular ectopy and dysmorphic features. {ECO:0000269|PubMed:11371347, ECO:0000269|PubMed:12148092, ECO:0000269|PubMed:12163457, ECO:0000269|PubMed:16571646, ECO:0000269|PubMed:17324964}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short QT syndrome 3 (SQT3) [MIM:609622]: A heart disorder characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. It causes syncope and sudden death. SQT3 has a unique ECG phenotype characterized by asymmetrical T waves. {ECO:0000269|PubMed:15761194}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrial fibrillation, familial, 9 (ATFB9) [MIM:613980]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:15922306}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.221
Intolerance Scores
- LoFtool
- 0.0226
- RVIS EVS
- -0.58
- RVIS percentile EVS
- 18.44
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.797
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |