PRKG1

protein kinase cGMP-dependent 1, the group of MicroRNA protein coding host genes|AGC family kinases

Basic information

Region (hg38): 10:50990887-52298423

Previous symbols: [ "PRKGR1B", "PRKG1B" ]

Links

ENSG00000185532 ∙ NCBI:5592 ∙ OMIM:176894 ∙ HGNC:9414 ∙ Uniprot:Q13976 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• aortic aneurysm, familial thoracic 8 (Strong), mode of inheritance: AD
• aortic aneurysm, familial thoracic 8 (Moderate), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Supportive), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Aortic aneurysm, familial thoracic 8	AD	Cardiovascular	Individuals have been described as suffering from sudden death secondary to aortic dissection/rupture, and surveillance and preventive measures, as well as early treatment of disease-related manifestations (including aortic aneurysms as well as other vascular anomalies), may help ameloriate morbidity and mortality	Cardiovascular	16646045; 23910461

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PRKG1 gene.

• Aortic aneurysm, familial thoracic 8 (359 variants)
• not provided (186 variants)
• Familial thoracic aortic aneurysm and aortic dissection (177 variants)
• not specified (48 variants)
• Inborn genetic diseases (33 variants)
• Connective tissue disorder (12 variants)
• PRKG1-related condition (3 variants)
• Gestational diabetes mellitus uncontrolled (1 variants)
• Cardiovascular phenotype (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRKG1 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			3	159	5	167
missense	1		196	2		199
nonsense			2			2
start loss						0
frameshift						0
inframe indel			2			2
splice donor/acceptor (+/-2bp)			2			2
splice region			17	20		37
non coding			24	90	59	173
Total	1	0	229	251	64

Variants in PRKG1

This is a list of pathogenic ClinVar variants found in the PRKG1 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-50990905-C-T			Benign (Jun 18, 2018)
10-50991019-TA-T			Benign (Jul 08, 2018)
10-50991034-A-G			Likely benign (Jun 19, 2018)
10-50991227-A-G			Likely benign (Jun 14, 2018)
10-50991235-C-A			Likely benign (Jun 14, 2018)
10-50991304-C-A			Likely benign (Aug 07, 2018)
10-50991310-AGCCGCCGCC-A			Benign (Aug 18, 2019)
10-50991310-A-AGCC			Benign (Nov 19, 2019)
10-50991310-A-AGCCGCC			Likely benign (Aug 13, 2019)
10-50991310-A-AGCCGCCGCCGCC			Benign (Nov 19, 2019)
10-50991328-C-CGCT			Benign (Aug 10, 2019)
10-50991391-G-C		Aortic aneurysm, familial thoracic 8 • PRKG1-related disorder	Benign/Likely benign (Jul 30, 2020)
10-50991417-G-A		Familial thoracic aortic aneurysm and aortic dissection • Aortic aneurysm, familial thoracic 8 • PRKG1-related disorder	Likely benign (Mar 02, 2024)
10-50991469-G-A		PRKG1-related disorder	Uncertain significance (Aug 22, 2023)
10-50991509-A-G		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Dec 28, 2023)
10-50991519-C-G		PRKG1-related disorder	Likely benign (Oct 14, 2019)
10-50991522-A-C		PRKG1-related disorder	Likely benign (Oct 14, 2019)
10-50991587-C-G		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jul 19, 2023)
10-50991624-G-C			Uncertain significance (Apr 01, 2017)
10-50991636-G-A		PRKG1-related disorder	Likely benign (May 31, 2019)
10-50991679-C-T			Likely benign (Aug 14, 2018)
10-50991696-G-C			Likely benign (Jul 26, 2018)
10-50991778-C-A			Likely benign (Aug 07, 2018)
10-51074142-C-T			Benign (Jun 16, 2018)
10-51074316-C-G			Likely benign (Jun 28, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PRKG1	protein_coding	protein_coding	ENST00000373980	18	1307166

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000623	125722	0	7	125729	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.98	211	373	0.566	0.0000184	4538
Missense in Polyphen		58	130.27	0.44524		1703
Synonymous	-0.931	150	136	1.10	0.00000713	1241
Loss of Function	5.19	4	38.9	0.103	0.00000190	490

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000291	0.0000291
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000945	0.0000924
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine protein kinase that acts as key mediator of the nitric oxide (NO)/cGMP signaling pathway. GMP binding activates PRKG1, which phosphorylates serines and threonines on many cellular proteins. Numerous protein targets for PRKG1 phosphorylation are implicated in modulating cellular calcium, but the contribution of each of these targets may vary substantially among cell types. Proteins that are phosphorylated by PRKG1 regulate platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes involved in several aspects of the CNS like axon guidance, hippocampal and cerebellar learning, circadian rhythm and nociception. Smooth muscle relaxation is mediated through lowering of intracellular free calcium, by desensitization of contractile proteins to calcium, and by decrease in the contractile state of smooth muscle or in platelet activation. Regulates intracellular calcium levels via several pathways: phosphorylates MRVI1/IRAG and inhibits IP3- induced Ca(2+) release from intracellular stores, phosphorylation of KCNMA1 (BKCa) channels decreases intracellular Ca(2+) levels, which leads to increased opening of this channel. PRKG1 phosphorylates the canonical transient receptor potential channel (TRPC) family which inactivates the associated inward calcium current. Another mode of action of NO/cGMP/PKGI signaling involves PKGI-mediated inactivation of the Ras homolog gene family member A (RhoA). Phosphorylation of RHOA by PRKG1 blocks the action of this protein in myriad processes: regulation of RHOA translocation; decreasing contraction; controlling vesicle trafficking, reduction of myosin light chain phosphorylation resulting in vasorelaxation. Activation of PRKG1 by NO signaling alters also gene expression in a number of tissues. In smooth muscle cells, increased cGMP and PRKG1 activity influence expression of smooth muscle-specific contractile proteins, levels of proteins in the NO/cGMP signaling pathway, down-regulation of the matrix proteins osteopontin and thrombospondin-1 to limit smooth muscle cell migration and phenotype. Regulates vasodilator-stimulated phosphoprotein (VASP) functions in platelets and smooth muscle. {ECO:0000269|PubMed:10567269, ECO:0000269|PubMed:11162591, ECO:0000269|PubMed:11723116, ECO:0000269|PubMed:12082086, ECO:0000269|PubMed:14608379, ECO:0000269|PubMed:15194681, ECO:0000269|PubMed:16990611, ECO:0000269|PubMed:8182057}.
• Disease: DISEASE: Aortic aneurysm, familial thoracic 8 (AAT8) [MIM:615436]: A disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance. {ECO:0000269|PubMed:23910461}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Platelet activation - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Long-term depression - Homo sapiens (human);Gap junction - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Salivary secretion - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Olfactory transduction - Homo sapiens (human);MicroRNAs in cardiomyocyte hypertrophy;Cardiac Hypertrophic Response;VEGFA-VEGFR2 Signaling Pathway;Signaling by WNT;Signal Transduction;ion channels and their functional role in vascular endothelium;Immune System;Rap1 signalling;Adaptive Immune System;actions of nitric oxide in the heart;IL-7 signaling;Ca2+ pathway;Beta-catenin independent WNT signaling;Hemostasis;Thromboxane A2 receptor signaling;JAK STAT pathway and regulation;EPO signaling;cGMP effects;Nitric oxide stimulates guanylate cyclase;VEGF;Platelet homeostasis;Regulation of p38-alpha and p38-beta (Consensus)

Recessive Scores

• pRec: 0.707

Intolerance Scores

• loftool: 0.0367
• rvis_EVS: -0.8
• rvis_percentile_EVS: 12.46

Haploinsufficiency Scores

• pHI: 0.987
• hipred: Y
• hipred_score: 0.814
• ghis: 0.594

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.985

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Prkg1
• Phenotype: muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; immune system phenotype; reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic 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)

Gene ontology

• Biological process: neuron migration;protein phosphorylation;signal transduction;dendrite development;cGMP-mediated signaling;actin cytoskeleton organization;forebrain development;regulation of GTPase activity;relaxation of vascular smooth muscle;negative regulation of platelet aggregation;negative regulation of vascular smooth muscle cell proliferation;negative regulation of vascular associated smooth muscle cell migration
• Cellular component: cytoplasm;Golgi apparatus;cytosol;plasma membrane
• Molecular function: protein kinase activity;protein serine/threonine kinase activity;cGMP-dependent protein kinase activity;calcium channel regulator activity;protein binding;ATP binding;cGMP binding