PRKAB2
protein-codingprotein kinase AMP-activated non-catalytic subunit beta 2
Gene summary
The protein encoded by this gene is a regulatory subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. This subunit may be a positive regulator of AMPK activity. It is highly expressed in skeletal muscle and thus may have tissue-specific roles. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0005453
Submitter: ClinGen
*PRKAB2* was first reported in relation to congenital heart disease in 2004 (Christiansen J et al, PMID: 15117819). Individuals with structural heart defects and copy number variants involving *PRKAB2* have been reported. These CNVs have been reported in individuals with congenital cardiac malformations including Tetralogy of Fallot, aortic arch obstruction, and other structural cardiac defects (PMIDs: 15117819, 31340305). No convincing reports of single-gene pathogenic variants in *PRKAB2* have been demonstrated to cause isolated congenital heart disease, and the contribution of *PRKAB2* to the cardiac phenotypes observed in CNVs remains uncertain. Additionally, experimental evidence directly linking *PRKAB2* to structural cardiac defects is limited. In summary, the evidence supporting the relationship between *PRKAB2* and congenital heart disease has been disputed, and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *PRKAB2* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date December 9th, 2024 (SOP Version 11).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PRKAB2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005399.5. 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 | 1 | 1 | ||||
| missense | 21 | 21 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 23 | 0 | 0 | 23 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005390.1 | 7 | MANE Select | |
| Ensembl | ENSP00000254101.3 | 7 | MANE Select | |
| Ensembl | ENSP00000566060.1 | 7 | Standard | |
| Ensembl | ENSP00000566061.1 | 7 | 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
- protein phosphorylation
- fatty acid biosynthetic process
- cell cycle arrest
- signal transduction
- macroautophagy
Molecular Function
- AMP-activated protein kinase activity
- protein binding
- protein kinase binding
- identical protein binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
- nucleotide-activated protein kinase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000254101
- Coding exons
- 7
- Length
- 17445
- Individuals with no LoFs
- 125738
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125742
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.50 | 97 | 148 | 0.654 | 0.00000723 | 1777 |
| Missense (PolyPhen) | 46 | 67.302 | 0.68349 | 796 | ||
| Synonymous | 0.382 | 53 | 56.7 | 0.935 | 0.00000281 | 516 |
| Loss of Function | 2.82 | 2 | 13.0 | 0.154 | 6.13e-7 | 157 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.0000088 | rare |
| South Asian | 0.000066 | 0.000065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-catalytic 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. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).;
Recessive Scores
- pRec
- 0.174
Intolerance Scores
- LoFtool
- 0.226
- RVIS EVS
- 0.19
- RVIS percentile EVS
- 66.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.368
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |