GeneBe

PRKAR1A

protein-coding

protein kinase cAMP-dependent type I regulatory subunit alpha, the group of Protein kinase A subunits

Gene summary

cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]

Previous symbols:
  • PRKAR1
  • TSE1

MANE transcript

NM_002734.5

Inheritance

AD

ClinVar variants

P:116U:528B:337

Top phenotype

Pigmented nodular adrenocortical disease, primary, 1; Carney complex, type 1; Myxoma, intracardiac; Acrodysostosis 1, with or without hormone resistance

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:68,511,780-68,551,319

External References & Databases

Ensembl (ENSG00000108946)NCBI Gene (5573)OMIM (188830)HGNC:9388GenCCUniProt (P10644)AlphaFoldClinVar (PRKAR1A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~39.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pigmented nodular adrenocortical disease, primary, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012509

Submitter: Genomics England PanelApp

Carney complex, type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008057

Submitter: ClinGen

There is abundant evidence published associating the PRKAR1A gene with Carney complex, type 1, since the gene-disease relationship was first proposed by Kirschner et al. (2000). Multiple case level studies have been performed with CNC patients that have variants in the PRKAR1A gene. Western-blot analysis of primary cell lines from multiple patients indicate that nonsense and frameshift mutations led to NMD. prkar1a +/− mice exhibited extracardiac tumorigenesis, developed sarcomas and hepatocellular carcinomas as well as thyroid, adrenocortical and mesenchymal tumors, which sharing similar phenotypes to CNC patients. In patient cells from three families, both the stimulation of kinase activity with cAMP and the inhibition of that stimulation by PKI were greater in CNC tumours than in those in the control samples. All of these types of evidence are consistent with a definitive relationship between the PRKAR1A gene and Carney complex, type 1.

familial atrial myxomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009719

Submitter: Orphanet

acrodysostosis with multiple hormone resistanceDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017240

Submitter: Illumina

Carney complexSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015285

Submitter: Orphanet

acrodysostosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019797

Submitter: Orphanet

Acrodysostosis 1 with or without hormone resistanceDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007044

Submitter: G2P

Carney complex, type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008057

Submitter: Labcorp Genetics (formerly Invitae)

Acrodysostosis 1 with or without hormone resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007044

Submitter: Labcorp Genetics (formerly Invitae)

Acrodysostosis 1 with or without hormone resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007044

Submitter: PanelApp Australia

Carney complex, type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008057

Submitter: PanelApp Australia

familial atrial myxomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009719

Submitter: PanelApp Australia

Acrodysostosis 1 with or without hormone resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007044

Submitter: Ambry Genetics

Carney complex, type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008057

Submitter: Ambry Genetics

pigmented nodular adrenocortical disease, primary, 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012509

Submitter: Ambry Genetics

Carney complex, type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008057

Submitter: G2P

pigmented nodular adrenocortical disease, primary, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012509

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Pigmented nodular adrenocortical disease, primary, 1; Carney complex, type 1; Myxoma, intracardiac; Acrodysostosis 1, with or without hormone resistanceAD

Manifestation: Cardiovascular; Dermatologic; Endocrine; Musculoskeletal; Neurologic; Oncologic

Intervention: Endocrine; Oncologic

Rationale: Surveillance for neoplasms (eg, cardiac myxomas), as well as multiple endocrine-related manifestations can allow early detection and treatment, which can involve surgical excision of the neoplasm; Additional surveillance for endocrine abnormalities can allow early interventions

Refs: 1263542; 579530; 6329005; 4010501; 3465316; 3365080; 2605794; 2586567; 1571257; 9415461; 9215269; 9805140; 10523219; 10974026; 10973256; 11549623; 12213893; 20507346; 21651393; 22464252; 22464250; 20301463Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRKAR1A variants in ClinVar

15 Conditions Cataloged
Carney complex, type 1Total: 920
Hereditary cancer-predisposing syndromeTotal: 716
not providedTotal: 146
not specifiedTotal: 90
Acrodysostosis 1 with or without hormone resistanceTotal: 68
PRKAR1A-related disorderTotal: 30
Familial atrial myxomaTotal: 29
Pigmented nodular adrenocortical disease, primary, 1Total: 24

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002734.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
321
clinvar
 322
missense
6
clinvar
7
clinvar
513
clinvar
13
clinvar
2
clinvar
 541
nonsense
19
clinvar
4
clinvar
3
clinvar
 26
start loss
1
clinvar
1
clinvar
 2
frameshift
44
clinvar
8
clinvar
1
clinvar
 53
splice donor/acceptor (+/-2bp)
10
clinvar
16
clinvar
10
clinvar
1
clinvar
 37
Total80365283352981

Highest pathogenic variant AF is 0.0000020800485

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 94 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002734.5RefSeqNP_002725.110MANE Select
ENST00000589228.6EnsemblENSP00000464977.210MANE Select
NM_001276289.2RefSeqNP_001263218.110Standard
NM_001276290.1RefSeqNP_001263219.110Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
prkar1aaDanio rerio

Structure: protein kinase activity

Quality: increased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Insulin signaling pathway - Homo sapiens (human)
  • Disopyramide Action Pathway
  • Procainamide (Antiarrhythmic) Action Pathway
  • Phenytoin (Antiarrhythmic) Action Pathway
  • Fosphenytoin (Antiarrhythmic) Action Pathway

Biological Process

  • mesoderm formation
  • renal water homeostasis
  • regulation of transcription by RNA polymerase II
  • female meiotic nuclear division
  • blood coagulation

Molecular Function

  • cAMP-dependent protein kinase inhibitor activity
  • protein binding
  • cAMP-dependent protein kinase regulator activity
  • protein domain specific binding
  • cAMP binding

Cellular Component

  • immunological synapse
  • cytoplasm
  • cytosol
  • axoneme
  • cAMP-dependent protein kinase complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000589228
Coding exons
10
Length
39540
Individuals with no LoFs
125732
Homozygous LoFs
0
Heterozygous LoFs
9
Defined
125741
p
0.0000358
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.12892190.4060.00001322478
Missense (PolyPhen)753.0970.13184613
Synonymous-2.1110379.11.300.00000466744
Loss of Function4.64025.10.000.00000164261

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000440.000044rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. {ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:20215566, ECO:0000269|PubMed:26405036}.;
Disease
DISEASE: Carney complex 1 (CNC1) [MIM:160980]: CNC is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas. {ECO:0000269|PubMed:15371594, ECO:0000269|PubMed:18241045, ECO:0000269|PubMed:22785148, ECO:0000269|PubMed:23323113, ECO:0000269|PubMed:26405036}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Intracardiac myxoma (INTMYX) [MIM:255960]: Inheritance is autosomal recessive. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Primary pigmented nodular adrenocortical disease 1 (PPNAD1) [MIM:610489]: 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. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. PPNAD1 is most often diagnosed in patients with Carney complex, a multiple neoplasia syndrome. However it can also be observed in patients without other manifestations. {ECO:0000269|PubMed:12213893}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Acrodysostosis 1, with or without hormone resistance (ACRDYS1) [MIM:101800]: A form of skeletal dysplasia characterized by short stature, severe brachydactyly, facial dysostosis, and nasal hypoplasia. Affected individuals often have advanced bone age and obesity. Laboratory studies show resistance to multiple hormones, including parathyroid, thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin. However, not all patients show endocrine abnormalities. {ECO:0000269|PubMed:21651393, ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:22723333, ECO:0000269|PubMed:23043190, ECO:0000269|PubMed:23425300, ECO:0000269|PubMed:26405036}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.727

Intolerance Scores

LoFtool
0.0537
RVIS EVS
-0.34
RVIS percentile EVS
30.07

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.994

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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