PRKAG2
protein-codingprotein kinase AMP-activated non-catalytic subunit gamma 2
Gene summary
AMP-activated protein kinase (AMPK) is a heterotrimeric protein composed of a catalytic alpha subunit, a noncatalytic beta subunit, and a noncatalytic regulatory gamma subunit. Various forms of each of these subunits exist, encoded by different genes. AMPK is an important energy-sensing enzyme that monitors cellular energy status and functions by inactivating key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. This gene is a member of the AMPK gamma subunit family. Mutations in this gene have been associated with Wolff-Parkinson-White syndrome, familial hypertrophic cardiomyopathy, and glycogen storage disease of the heart. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~321.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0010946
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0800484
Submitter: ClinGen
The PRKAG2 gene is associated with PRKAG2-related cardiomyopathy, an autosomal dominant disease characterized by heart-specific glycogenesis, ventricular pre-excitation, supraventricular tachyarrhythmias, and cardiac hypertrophy (Burwinkel et al., 2005, PMID 15877279). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: [Cardiomyopathy, hypertrophic 6] (OMIM: 600858), [Glycogen storage disease of heart, lethal congenital] (OMIM: 261740), [Wolff-Parkinson-White syndrome] (OMIM: 194200). PRKAG2 variants mainly affect the heart, but some studies have reported skeletal myopathy with elevated creatine phosphokinase (Murphy et al., 2005, PMID 15766830; Laforet et al., 2006, PMID 16487706). PRKAG2 encodes the non-catalytic γ subunit of AMPK, a protein kinase that when activated by cellular stress, leads to increased AMP levels and reduced ATP levels. Variants in PRKAG2 are hypothesized to modify the structure of AMPK, altering its affinity for AMP (reviewed in Porto et al., 2016, PMID 26729852). More than 190 individuals comprising at least 13 different variants in PRKAG2 have been reported in the literature, almost all of which are missense variants (Porto et al., 2016, PMID 26729852). 18 variants (17 missense, 1 insertion) that have been reported in 19 probands in 12 publications (PMIDs: 23741347, 11371514, 11827995, 19787389, 16487706, 18403758, 15673802, 28546535, 32259713, 15877279, 31720784, 35588295) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The gene-disease relationship is also supported by expression studies, in vitro functional assays, and model systems (PMIDs: 11112354, 28009297, 17667862, 15877279, 28917552, 28917552, 16339829, 15611370). In summary, there is definitive evidence supporting the relationship between PRKAG2 and autosomal dominant PRKAG2-related cardiomyopathy. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy GCEP on April 4, 2017. It was reevaluated by the Hereditary Cardiovascular Disease GCEP on June 14, 2022 (SOP Version 9). As a result of this reevaluation, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0008685
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0010946
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008685
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009867
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Renal
Intervention: Cardiovascular
Rationale: Surveillance measures (eg, including echocardiography and electrocardiography) and medical and preventive management related to cardiac hypertrophy, as well as arrhythmia, may ameliorate/prevent severe sequelae
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PRKAG2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016203.4. 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 | 4 | 309 | 6 | 319 | ||
| missense | 13 | 21 | 572 | 57 | 6 | 669 |
| nonsense | 18 | 18 | ||||
| start loss | 3 | 3 | ||||
| frameshift | 19 | 19 | ||||
| splice donor/acceptor (+/-2bp) | 22 | 22 | ||||
| Total | 13 | 21 | 638 | 366 | 12 | 1050 |
Highest pathogenic variant AF is 0.0000065711656
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057287.2 | 16 | MANE Select | |
| Ensembl | ENSP00000287878.3 | 16 | MANE Select | |
| RefSeq | NP_001035723.1 | 15 | Standard | |
| RefSeq | NP_001291456.1 | 14 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Oxytocin signaling pathway - Homo sapiens (human)
- Adipocytokine signaling pathway - Homo sapiens (human)
- Circadian rhythm - Homo sapiens (human)
- Insulin resistance - Homo sapiens (human)
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Biological Process
- glycogen metabolic process
- regulation of glycolytic process
- protein phosphorylation
- negative regulation of protein kinase activity
- fatty acid biosynthetic process
Molecular Function
- AMP-activated protein kinase activity
- cAMP-dependent protein kinase inhibitor activity
- ATP binding
- cAMP-dependent protein kinase regulator activity
- phosphorylase kinase regulator activity
Cellular Component
- extracellular space
- nucleoplasm
- cytosol
- nucleotide-activated protein kinase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000287878
- Coding exons
- 16
- Length
- 321014
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125748
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.65 | 242 | 326 | 0.742 | 0.0000189 | 3695 |
| Missense (PolyPhen) | 36 | 88.496 | 0.4068 | 983 | ||
| Synonymous | -0.240 | 134 | 131 | 1.03 | 0.00000846 | 1124 |
| Loss of Function | 4.59 | 3 | 30.2 | 0.0992 | 0.00000170 | 357 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive. {ECO:0000269|PubMed:14722619}.;
- Disease
- DISEASE: Wolff-Parkinson-White syndrome (WPWS) [MIM:194200]: A supernormal conduction disorder characterized by the presence of one or several accessory atrioventricular connections, which can lead to episodes of sporadic tachycardia. {ECO:0000269|PubMed:11407343, ECO:0000269|PubMed:11748095, ECO:0000269|PubMed:14722619}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial hypertrophic 6 (CMH6) [MIM:600858]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. CMH6 patients present Wolff-Parkinson-White ventricular preexcitation, enlarged myocytes without myofiber disarray, and glycogen- containing cytosolic vacuoles within cardiomyocytes. {ECO:0000269|PubMed:11371514, ECO:0000269|PubMed:11827995}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glycogen storage disease of heart lethal congenital (GSDH) [MIM:261740]: Rare disease which leads to death within a few weeks to a few months after birth, through heart failure and respiratory compromise. {ECO:0000269|PubMed:15877279}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.194
Intolerance Scores
- LoFtool
- 0.0134
- RVIS EVS
- -0.87
- RVIS percentile EVS
- 10.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.876
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |