PRKAG2

protein kinase AMP-activated non-catalytic subunit gamma 2

Basic information

Region (hg38): 7:151556123-151877125

Links

ENSG00000106617 ∙ NCBI:51422 ∙ OMIM:602743 ∙ HGNC:9386 ∙ Uniprot:Q9UGJ0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypertrophic cardiomyopathy 6 (Strong), mode of inheritance: AD
• Wolff-Parkinson-White syndrome (Strong), mode of inheritance: AD
• lethal congenital glycogen storage disease of heart (Strong), mode of inheritance: AD
• lethal congenital glycogen storage disease of heart (Strong), mode of inheritance: AD
• hypertrophic cardiomyopathy 6 (Definitive), mode of inheritance: AD
• Wolff-Parkinson-White syndrome (Strong), mode of inheritance: AD
• hypertrophic cardiomyopathy 6 (Strong), mode of inheritance: AD
• hypertrophic cardiomyopathy (Definitive), mode of inheritance: AD
• PRKAG2-related cardiomyopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiomyopathy, familial hypertrophic 6; Wolff-Parkinson-White syndrome	AD	Cardiovascular	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	Cardiovascular; Craniofacial; Musculoskeletal; Renal	13619017; 15371577; 10820940; 11371514; 11586962; 11827995; 15673802; 15877279; 16716659; 16487706; 18403758; 19787389

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PRKAG2 gene.

• Lethal congenital glycogen storage disease of heart (654 variants)
• Cardiomyopathy (364 variants)
• not provided (289 variants)
• Cardiovascular phenotype (219 variants)
• not specified (154 variants)
• Wolff-Parkinson-White pattern (109 variants)
• Hypertrophic cardiomyopathy 6 (94 variants)
• Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (24 variants)
• Hypertrophic cardiomyopathy (21 variants)
• Primary familial hypertrophic cardiomyopathy (11 variants)
• Lethal congenital glycogen storage disease of heart;Hypertrophic cardiomyopathy 6;Wolff-Parkinson-White pattern (8 variants)
• Wolff-Parkinson-White pattern;Lethal congenital glycogen storage disease of heart;Hypertrophic cardiomyopathy 6 (6 variants)
• Inborn genetic diseases (6 variants)
• PRKAG2-related condition (6 variants)
• Lethal congenital glycogen storage disease of heart;Wolff-Parkinson-White pattern;Hypertrophic cardiomyopathy 6 (5 variants)
• Hypertrophic cardiomyopathy 6;Wolff-Parkinson-White pattern;Lethal congenital glycogen storage disease of heart (3 variants)
• Hypertrophic cardiomyopathy 6;Lethal congenital glycogen storage disease of heart;Wolff-Parkinson-White pattern (2 variants)
• PRKAG2 cardiac syndrome (2 variants)
• Wolff-Parkinson-White pattern;Hypertrophic cardiomyopathy 6;Lethal congenital glycogen storage disease of heart (2 variants)
• Hypertrophic cardiomyopathy 1 (2 variants)
• Renal cysts and diabetes syndrome (1 variants)
• Congestive heart failure (1 variants)
• Arrhythmogenic right ventricular dysplasia 9 (1 variants)
• See cases (1 variants)
• PRKAG2-Related Disorders (1 variants)
• Heart failure (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Wolff-Parkinson-White syndrome, childhood-onset (1 variants)
• 6 conditions (1 variants)
• Left ventricular hypertrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRKAG2 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	187	4	193
missense	9	9	327	15	1	361
nonsense			7			7
start loss			2			2
frameshift			11			11
inframe indel			8			8
splice donor/acceptor (+/-2bp)			13			13
splice region			18	28		46
non coding			43	147	86	276
Total	9	9	413	349	91

Highest pathogenic variant AF is 0.00000657

Variants in PRKAG2

This is a list of pathogenic ClinVar variants found in the PRKAG2 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-151556140-C-T		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Benign (Jan 12, 2018)
7-151556158-C-T		Hypertrophic cardiomyopathy 6 • Wolff-Parkinson-White pattern	Uncertain significance (Jan 13, 2018)
7-151556159-T-TG		Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Lethal congenital glycogen storage disease of heart • Wolff-Parkinson-White pattern	Uncertain significance (Jun 14, 2016)
7-151556160-GA-G		Lethal congenital glycogen storage disease of heart • Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Wolff-Parkinson-White pattern	Uncertain significance (Jun 14, 2016)
7-151556160-G-GA		Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Lethal congenital glycogen storage disease of heart • Wolff-Parkinson-White pattern	Uncertain significance (Jun 14, 2016)
7-151556171-A-C		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Conflicting classifications of pathogenicity (Mar 01, 2023)
7-151556171-A-AC		Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Lethal congenital glycogen storage disease of heart • Wolff-Parkinson-White pattern	Uncertain significance (Jun 14, 2016)
7-151556179-CA-AC		Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Lethal congenital glycogen storage disease of heart • Wolff-Parkinson-White pattern	Uncertain significance (Jun 14, 2016)
7-151556179-CA-C		Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Lethal congenital glycogen storage disease of heart • Wolff-Parkinson-White pattern	Likely benign (Jun 14, 2016)
7-151556180-A-C		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Uncertain significance (Jan 12, 2018)
7-151556189-A-C		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Uncertain significance (Jan 13, 2018)
7-151556237-C-T		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Uncertain significance (Jan 13, 2018)
7-151556248-A-T		Hypertrophic cardiomyopathy 6 • Wolff-Parkinson-White pattern	Uncertain significance (Feb 04, 2019)
7-151556304-CA-C		Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome • Lethal congenital glycogen storage disease of heart • Wolff-Parkinson-White pattern	Conflicting classifications of pathogenicity (Jun 01, 2023)
7-151556314-C-T		Hypertrophic cardiomyopathy 6 • Wolff-Parkinson-White pattern	Uncertain significance (Jan 13, 2018)
7-151556366-A-G		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Uncertain significance (Jan 13, 2018)
7-151556430-G-A		Hypertrophic cardiomyopathy 6 • Wolff-Parkinson-White pattern	Uncertain significance (Jan 13, 2018)
7-151556587-T-A		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Conflicting classifications of pathogenicity (May 01, 2023)
7-151556589-C-T		Hypertrophic cardiomyopathy 6 • Wolff-Parkinson-White pattern	Uncertain significance (Jan 12, 2018)
7-151556629-C-T		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Likely benign (Jan 13, 2018)
7-151556679-C-A		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Benign (Jan 13, 2018)
7-151556730-A-G		Hypertrophic cardiomyopathy 6 • Wolff-Parkinson-White pattern	Uncertain significance (Jan 12, 2018)
7-151556749-G-A		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Benign/Likely benign (Jan 13, 2018)
7-151556751-A-G		Hypertrophic cardiomyopathy 6 • Wolff-Parkinson-White pattern	Uncertain significance (Jan 13, 2018)
7-151556782-G-A		Wolff-Parkinson-White pattern • Hypertrophic cardiomyopathy 6	Uncertain significance (Apr 27, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PRKAG2	protein_coding	protein_coding	ENST00000287878	16	321014

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.997	0.00308	125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.65	242	326	0.742	0.0000189	3695
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000905	0.0000904
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000535	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Longevity regulating pathway - multiple species - Homo sapiens (human);Tight junction - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Metformin Pathway, Pharmacodynamic;AMP-activated Protein Kinase (AMPK) Signaling;Target Of Rapamycin (TOR) Signaling;Energy Metabolism;Sterol Regulatory Element-Binding Proteins (SREBP) signalling;Ectoderm Differentiation;Angiopoietin Like Protein 8 Regulatory Pathway;Lipid Metabolism Pathway;Liver steatosis AOP;Signal Transduction;Gene expression (Transcription);Vesicle-mediated transport;reversal of insulin resistance by leptin;chrebp regulation by carbohydrates and camp;Membrane Trafficking;Generic Transcription Pathway;Metabolism of lipids;AMPK inhibits chREBP transcriptional activation activity;Import of palmitoyl-CoA into the mitochondrial matrix;RNA Polymerase II Transcription;Energy dependent regulation of mTOR by LKB1-AMPK;mTOR signalling;Metabolism;Fatty acid metabolism;insulin Mam;TP53 Regulates Metabolic Genes;Macroautophagy;Cellular responses to external stimuli;IL-7 signaling;JAK STAT pathway and regulation;EPO signaling;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Activation of PPARGC1A (PGC-1alpha) by phosphorylation;Mitochondrial biogenesis;Translocation of GLUT4 to the plasma membrane;Integration of energy metabolism;VEGF;insulin;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.194

Intolerance Scores

• loftool: 0.0134
• rvis_EVS: -0.87
• rvis_percentile_EVS: 10.73

Haploinsufficiency Scores

• pHI: 0.758
• hipred: Y
• hipred_score: 0.825
• ghis: 0.557

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.876

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Prkag2
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system 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); immune system phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; muscle phenotype

Gene ontology

• Biological process: glycogen metabolic process;regulation of glycolytic process;protein phosphorylation;negative regulation of protein kinase activity;fatty acid biosynthetic process;ATP biosynthetic process;cell cycle arrest;positive regulation of peptidyl-threonine phosphorylation;sterol biosynthetic process;macroautophagy;regulation of fatty acid metabolic process;activation of protein kinase activity;intracellular signal transduction;regulation of fatty acid biosynthetic process;positive regulation of protein kinase activity;regulation of fatty acid oxidation;regulation of glucose import;negative regulation of protein serine/threonine kinase activity
• Cellular component: extracellular space;nucleoplasm;cytosol;nucleotide-activated protein kinase complex
• 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;AMP binding;protein kinase binding;protein kinase activator activity;ADP binding