PRKACA
protein kinase cAMP-activated catalytic subunit alpha, the group of Protein kinase A subunits|AGC family kinases
Basic information
Region (hg38): 19:14091687-14118084
Links
Phenotypes
GenCC
Source:
- cardioacrofacial dysplasia 1 (Limited), mode of inheritance: AD
- pigmented nodular adrenocortical disease, primary, 4 (Limited), mode of inheritance: Unknown
- cardioacrofacial dysplasia 1 (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Primary pigmented nodular adrenocortical disease 4;Cardioacrofacial dysplasia 1 | AD | Cardiovascular; Endocrine | In Primary pigmented nodular adrenocortical disease 4, awareness may allow early management of adrenal disease (eg, potentially including surgical intervention), which may be beneficial; Cardioacrofacial dysplasia 1 may include congenital cardiovascular anomalies (among other features), and awareness may allow prompt recognition and management of these issues | Cardiovascular; Craniofacial; Dental; Endocrine; Musculoskeletal | 24571724; 24700472; 24747643; 33058759 |
| Mosaicism has been described in Cardioacrofacial dysplasia 1 |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (15 variants)
- Inborn genetic diseases (5 variants)
- Cardioacrofacial dysplasia 1 (3 variants)
- Neurodevelopmental disorder (1 variants)
- PRKACA-related condition (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRKACA 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 | 11 | |||||
| missense | 10 | 11 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region ? | 1 | 1 | ||||
| non coding ? | 1 | |||||
| Total | 0 | 1 | 10 | 9 | 3 |
Variants in PRKACA
This is a list of pathogenic ClinVar variants found in the PRKACA region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 19-14093146-T-C | Cardioacrofacial dysplasia 1 | Uncertain significance (Aug 26, 2023) | ||
| 19-14093172-C-T | Likely benign (Oct 01, 2023) | |||
| 19-14093679-C-A | not specified | Uncertain significance (May 04, 2022) | ||
| 19-14093683-A-G | Cardioacrofacial dysplasia 1 | Uncertain significance (Mar 26, 2024) | ||
| 19-14093688-G-A | Likely benign (May 23, 2018) | |||
| 19-14093699-T-C | not specified | Uncertain significance (Jul 15, 2021) | ||
| 19-14093715-G-C | Benign (Dec 31, 2019) | |||
| 19-14093747-G-A | Uncertain significance (Feb 01, 2023) | |||
| 19-14093768-A-G | not specified | Uncertain significance (Apr 26, 2023) | ||
| 19-14097373-G-A | PRKACA-related disorder | Likely benign (Sep 09, 2019) | ||
| 19-14097394-G-A | PRKACA-related disorder | Likely benign (May 08, 2019) | ||
| 19-14097415-C-T | PRKACA-related disorder | Likely benign (Apr 01, 2019) | ||
| 19-14097594-C-A | Cardioacrofacial dysplasia 1 | Uncertain significance (Aug 26, 2021) | ||
| 19-14097597-A-C | Likely benign (Mar 29, 2018) | |||
| 19-14097604-A-C | Pigmented nodular adrenocortical disease, primary, 4 • ACTH-independent adrenal Cushing syndrome, somatic | Pathogenic/Likely pathogenic (Jun 01, 2014) | ||
| 19-14097621-G-A | Likely benign (Nov 01, 2022) | |||
| 19-14097621-G-GCAC | Pigmented nodular adrenocortical disease, primary, 4 | Pathogenic (Mar 13, 2014) | ||
| 19-14097630-C-A | not specified | Uncertain significance (Dec 02, 2022) | ||
| 19-14097770-G-A | Likely benign (Dec 31, 2019) | |||
| 19-14097778-G-T | not specified | Uncertain significance (Jan 17, 2024) | ||
| 19-14100836-C-T | Cardioacrofacial dysplasia 1 | Pathogenic/Likely pathogenic (Jul 08, 2022) | ||
| 19-14100864-C-T | Benign (Dec 31, 2019) | |||
| 19-14100917-A-G | Likely benign (Apr 10, 2018) | |||
| 19-14102831-G-C | Likely benign (Jul 01, 2022) | |||
| 19-14106800-G-C | PRKACA-related disorder | Uncertain significance (Jul 09, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| PRKACA | protein_coding | protein_coding | ENST00000308677 | 10 | 26397 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.971 | 0.0286 | 125734 | 0 | 2 | 125736 | 0.00000795 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.97 | 92 | 214 | 0.429 | 0.0000136 | 2331 |
| Missense in Polyphen | 26 | 86.582 | 0.30029 | 885 | ||
| Synonymous | -0.221 | 92 | 89.3 | 1.03 | 0.00000632 | 637 |
| Loss of Function | 3.71 | 2 | 19.8 | 0.101 | 9.39e-7 | 230 |
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 | 0.00 | 0.00 |
| European (Non-Finnish) | 0.00000880 | 0.00000879 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose- mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B- alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha- difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). {ECO:0000269|PubMed:15642694, ECO:0000269|PubMed:15905176, ECO:0000269|PubMed:16387847, ECO:0000269|PubMed:17333334, ECO:0000269|PubMed:17565987, ECO:0000269|PubMed:17693412, ECO:0000269|PubMed:18836454, ECO:0000269|PubMed:19949837, ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:21085490, ECO:0000269|PubMed:21423175, ECO:0000269|PubMed:21514275, ECO:0000269|PubMed:21812984}.;
- Disease
- DISEASE: Primary pigmented nodular adrenocortical disease 4 (PPNAD4) [MIM:615830]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:24571724, ECO:0000269|PubMed:24700472, ECO:0000269|PubMed:24747643, ECO:0000269|PubMed:24855271}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Prion diseases - Homo sapiens (human);Inflammatory mediator regulation of TRP channels - Homo sapiens (human);Platelet activation - Homo sapiens (human);Cortisol synthesis and secretion - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Retrograde endocannabinoid signaling - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Oocyte meiosis - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Thyroid hormone synthesis - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);Tight junction - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Bile secretion - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);Vasopressin-regulated water reabsorption - Homo sapiens (human);Gap junction - Homo sapiens (human);Gastric acid secretion - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Amoebiasis - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human);Renin secretion - Homo sapiens (human);Vibrio cholerae infection - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Salivary secretion - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Taste transduction - Homo sapiens (human);Olfactory transduction - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Ovarian steroidogenesis - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics;Human papillomavirus infection - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);Hedgehog signaling pathway - Homo sapiens (human);Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;WNT-Core;HH-Core;EGF-Ncore;Nicotine Activity on Dopaminergic Neurons;Sterol Regulatory Element-Binding Proteins (SREBP) signalling;miRs in Muscle Cell Differentiation;Follicle Stimulating Hormone (FSH) signaling pathway;Regulation of Microtubule Cytoskeleton;Dopamine metabolism;Common Pathways Underlying Drug Addiction;Human Complement System;Mesodermal Commitment Pathway;IL-3 Signaling Pathway;Myometrial Relaxation and Contraction Pathways;G Protein Signaling Pathways;MAPK Signaling Pathway;Lipid Metabolism Pathway;Liver steatosis AOP;Ras Signaling;Hedgehog Signaling Pathway;Endochondral Ossification;Calcium Regulation in the Cardiac Cell;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Estrogen signaling pathway;Developmental Biology;Signaling by GPCR;Signal Transduction;Signaling by Interleukins;GLI3 is processed to GLI3R by the proteasome;HDL assembly;Plasma lipoprotein assembly;VEGFA-VEGFR2 Pathway;Metabolism of carbohydrates;Metabolism of lipids;Cytokine Signaling in Immune system;Glucagon signaling in metabolic regulation;PKA-mediated phosphorylation of key metabolic factors;GPCR Dopamine D1like receptor;Hedgehog;MAPK6/MAPK4 signaling;Factors involved in megakaryocyte development and platelet production;GPCR Adenosine A2A receptor;GPCR signaling-cholera toxin;CD209 (DC-SIGN) signaling;C-type lectin receptors (CLRs);Hedgehog;Innate Immune System;Immune System;Metabolism;Rap1 signalling;Adaptive Immune System;Ion homeostasis;PKA activation;PKA-mediated phosphorylation of CREB;Calmodulin induced events;CaM pathway;Transport of small molecules;Glucagon-like Peptide-1 (GLP1) regulates insulin secretion;Regulation of insulin secretion;Neuronal System;Aurora A signaling;Degradation of GLI2 by the proteasome;Degradation of GLI1 by the proteasome;Hedgehog ,off, state;Cardiac conduction;Muscle contraction;DARPP-32 events;Glycolysis;IL-7 signaling;GPCR signaling-G alpha s PKA and ERK;Signaling by Hedgehog;Regulation of PLK1 Activity at G2/M Transition;Triglyceride catabolism;Triglyceride metabolism;ROBO receptors bind AKAP5;SHP2 signaling;Recruitment of mitotic centrosome proteins and complexes;Glucocorticoid receptor regulatory network;Loss of Nlp from mitotic centrosomes;Loss of proteins required for interphase microtubule organization from the centrosome;Centrosome maturation;Hemostasis;DAG and IP3 signaling;AURKA Activation by TPX2;MAPK family signaling cascades;G2/M Transition;Mitotic G2-G2/M phases;Thromboxane A2 receptor signaling;JAK STAT pathway and regulation;EPO signaling;Signaling events regulated by Ret tyrosine kinase;IL3;Plasma lipoprotein assembly, remodeling, and clearance;Signaling by ROBO receptors;Recruitment of NuMA to mitotic centrosomes;Mitotic Prometaphase;Signaling by VEGF;Ca-dependent events;PLC beta mediated events;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;G-protein mediated events;Opioid Signalling;G alpha (i) signalling events;RET signaling;Axon guidance;M Phase;CREB phosphorylation through the activation of Adenylate Cyclase;Glucose metabolism;PKA activation in glucagon signalling;Post NMDA receptor activation events;Activation of NMDA receptor and postsynaptic events;Vasopressin regulates renal water homeostasis via Aquaporins;Aquaporin-mediated transport;Cell Cycle;Signaling by Receptor Tyrosine Kinases;Integration of energy metabolism;VEGF;Cell Cycle, Mitotic;GPCR downstream signalling;Anchoring of the basal body to the plasma membrane;ErbB2/ErbB3 signaling events;Intracellular signaling by second messengers;LPA4-mediated signaling events;GMCSF-mediated signaling events;Retinoic acid receptors-mediated signaling;Syndecan-1-mediated signaling events;Alpha4 beta1 integrin signaling events;Role of Calcineurin-dependent NFAT signaling in lymphocytes;Class I PI3K signaling events mediated by Akt;Signaling events mediated by HDAC Class I;Hedgehog signaling events mediated by Gli proteins;Signaling events mediated by VEGFR1 and VEGFR2;IL3-mediated signaling events;Calcium signaling in the CD4+ TCR pathway;Syndecan-2-mediated signaling events;LKB1 signaling events;VEGFR1 specific signals;Cilium Assembly;Organelle biogenesis and maintenance;Interleukin-3, 5 and GM-CSF signaling
(Consensus)
Recessive Scores
- pRec
- 0.535
Intolerance Scores
- loftool
- 0.0911
- rvis_EVS
- -0.47
- rvis_percentile_EVS
- 23.04
Haploinsufficiency Scores
- pHI
- 0.438
- hipred
- Y
- hipred_score
- 0.840
- ghis
- 0.583
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Prkaca
- Phenotype
- homeostasis/metabolism phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; renal/urinary system phenotype; skeleton phenotype; 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); 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); 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); reproductive system phenotype; neoplasm; embryo phenotype;
Gene ontology
- Biological process
- G2/M transition of mitotic cell cycle;mesoderm formation;neural tube closure;regulation of heart rate;stimulatory C-type lectin receptor signaling pathway;renal water homeostasis;mRNA processing;protein phosphorylation;blood coagulation;regulation of G2/M transition of mitotic cell cycle;protein kinase A signaling;regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion;regulation of macroautophagy;peptidyl-serine phosphorylation;peptidyl-threonine phosphorylation;cytokine-mediated signaling pathway;activation of protein kinase A activity;high-density lipoprotein particle assembly;cellular response to heat;calcium-mediated signaling using intracellular calcium source;regulation of protein binding;regulation of osteoblast differentiation;protein autophosphorylation;positive regulation of protein export from nucleus;sperm capacitation;modulation of chemical synaptic transmission;regulation of cytosolic calcium ion concentration;regulation of cardiac muscle contraction;regulation of ryanodine-sensitive calcium-release channel activity;regulation of proteasomal protein catabolic process;regulation of protein processing;positive regulation of cell cycle arrest;cellular response to glucose stimulus;cellular response to parathyroid hormone stimulus;cellular response to glucagon stimulus;cellular response to epinephrine stimulus;cell communication by electrical coupling involved in cardiac conduction;ciliary basal body-plasma membrane docking;negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning;regulation of cardiac conduction;regulation of bicellular tight junction assembly
- Cellular component
- acrosomal vesicle;nucleus;nucleoplasm;cytoplasm;mitochondrion;centrosome;cytosol;axoneme;cAMP-dependent protein kinase complex;membrane;nuclear speck;neuromuscular junction;calcium channel complex;sperm flagellum;dendritic spine;plasma membrane raft;intercellular bridge;perinuclear region of cytoplasm;extracellular exosome;ciliary base
- Molecular function
- magnesium ion binding;protein kinase activity;protein serine/threonine kinase activity;cAMP-dependent protein kinase activity;protein serine/threonine/tyrosine kinase activity;protein binding;ATP binding;protein kinase binding;protein domain specific binding;manganese ion binding;ubiquitin protein ligase binding;protein kinase A regulatory subunit binding