PRKACG

protein-coding

protein kinase cAMP-activated catalytic subunit gamma, the group of Protein kinase A subunits|AGC family kinases

Gene summary

Cyclic AMP-dependent protein kinase (PKA) consists of two catalytic subunits and a regulatory subunit dimer. This gene encodes the gamma form of its catalytic subunit. The gene is intronless and is thought to be a retrotransposon derived from the gene for the alpha form of the PKA catalytic subunit. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002732.4

Inheritance

ClinVar variants

U:63B:20

Top phenotype

Bleeding disorder, platelet-type, 19

gnomAD constraint

pLI —, LoF o/e —

Max pathogenic AF

—

Genomic locus

chr9:69,012,504-69,014,113

External References & Databases

Ensembl (ENSG00000165059)

Transcript & Mutation Effects

hg38 • Region Span ~1.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

platelet-type bleeding disorder 19LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014518

Submitter: Labcorp Genetics (formerly Invitae)

platelet-type bleeding disorder 19SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014518

Submitter: Orphanet

platelet-type bleeding disorder 19LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014518

Submitter: PanelApp Australia

platelet-type bleeding disorder 19NO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0014518

Submitter: ClinGen

The PRKACG gene, encoding the Protein Kinase CAMP-Activated Catalytic Subunit Gamma, was first associated with autosomal recessive platelet-type bleeding disorder 19 in 2014 by Manchev VT et al. (PMID: 25061177). This gene-disease relationship is supported by both genetic and experimental evidence. Case-level genetic evidence from the aforementioned study includes the identification of two siblings with a homozygous missense variant in PRKACG (c.222C>G, p.Ile74Met). Additionally, the proband had a missense variant in the GNE gene, which at the time was not associated with thrombocytopenia, leaving the GNE variant's role in the condition unexplored. Therefore, this case has not been classified as providing genetic-level evidence. Experimental evidence highlights the Functional Alteration in patient cells, where Filamin A (FLNa) was significantly reduced in mature megakaryocytes (MKs) and platelets of patients carrying the homozygous mutation in PRKACG. This suggests that PRKACG is crucial for FLNa phosphorylation. Furthermore, patients exhibited elevated cAMP levels, three to five times higher than controls, hinting at compromised protein kinase A (PKA) activity due to the PRKACG mutation.Rescue experiments in patient cells demonstrated that overexpressing wild-type PRKACG in MKs from patients with the PRKACG homozygous variant notably improved proplatelet (PPT) formation, in contrast to the null effects seen with the mutant PRKACG. The introduction of wild-type PRKACG also resulted in a significant reduction in the size of platelet-like structures along the PPTs, underscoring the disruption of the PKA pathway by the PRKACG mutation as a causative factor for thrombocytopenia. In summary, there is disputed evidence to support this gene-disease relationship. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on DATE (SOP Version 10).

Clinical Genomic Database (CGD)

Bleeding disorder, platelet-type, 19AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals have been described as manifesting with spontaneous bleeding episodes in childhood, and awareness may allow preventive measures and early management of bleeding diatheses

Refs: 25061177

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRKACG variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 71

not providedTotal: 17

PRKACG-related disorderTotal: 7

Platelet-type bleeding disorder 19Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002732.4. 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				19 clinvar	1 clinvar	20
missense			61 clinvar			61
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	63	19	1	83

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002732.4	RefSeq	NP_002723.2	1	MANE Select
ENST00000377276.5	Ensembl	ENSP00000366488.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

stimulatory C-type lectin receptor signaling pathway
renal water homeostasis
protein phosphorylation
spermatogenesis
blood coagulation

Molecular Function

protein serine/threonine kinase activity
cAMP-dependent protein kinase activity
ATP binding

Cellular Component

nucleoplasm
cytosol
intercellular bridge
ciliary base

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377276
Coding exons: 1
Length: 1571

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.182	232	224	1.03	0.0000165	2320
Missense (PolyPhen)		103	91.816	1.1218		976
Synonymous	0.805	94	104	0.900	0.00000900	688
Loss of Function

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Phosphorylates a large number of substrates in the cytoplasm and the nucleus.;

Recessive Scores

pRec: 0.277

Intolerance Scores

LoFtool: 0.648
RVIS EVS: -0.09
RVIS percentile EVS: 46.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.962

Gene Damage Prediction

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