PHKA2

protein-coding

phosphorylase kinase regulatory subunit alpha 2, the group of Phosphorylase kinase subunits

Gene summary

Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, and the hepatic isoform is encoded by this gene. The beta subunit is the same in both the muscle and hepatic isoforms, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, which are encoded by two different genes. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9A, also known as X-linked liver glycogenosis. Alternatively spliced transcript variants have been reported, but the full-length nature of these variants has not been determined.[provided by RefSeq, Feb 2010]

Previous symbols:

MANE transcript

NM_000292.3

Inheritance

AR, XL

ClinVar variants

P:139U:530B:171

Top phenotype

Glycogen storage disease, type IXa1

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chrX:18,892,298-18,984,114

External References & Databases

Ensembl (ENSG00000044446)

Transcript & Mutation Effects

hg38 • Region Span ~91.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease due to liver phosphorylase kinase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020693

Submitter: Orphanet

glycogen storage disease IXa1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010598

Submitter: Genomics England PanelApp

glycogen storage disease IXa1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010598

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease IXa1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010598

Submitter: PanelApp Australia

glycogen storage disease IXa1DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010598

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Glycogen storage disease, type IXa1XL

Manifestation: Biochemical; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Biochemical; Gastrointestinal

Rationale: The condition can include manifestations such as hypoglycemia, ketosis, and growth retardation, and recommendations for care include laboratory-based monitoring (eg, including liver function tests, glucose, and ketones), radiological monitoring (abdominal imaging), and nutritional recommendations and avoidance of certain medications in order to help improve metabolic to control and prevent the primary complications; Specific care during pregnancy has been recommended

Refs: 5306139; 4518931; 280544; 2303074; 7711737; 7847371; 8733134; 9600238; 9835437; 9870210; 10330341; 11286390; 12809646; 12862311; 16354226; 17581768; 17689125; 19856867; 21131218; 21646031; 21634085; 21844581; 21857251; 21911307; 24055370; 25266922; 30659246; 33317799

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHKA2 variants in ClinVar

16 Conditions Cataloged

Glycogen storage disease IXa1Total: 448

not providedTotal: 209

Inborn genetic diseasesTotal: 139

not specifiedTotal: 113

PHKA2-related disorderTotal: 62

Glycogen storage disease IXa2Total: 8

Glycogen storage diseaseTotal: 7

Glycogen phosphorylase kinase deficiencyTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000292.3. 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			51 clinvar	100 clinvar	10 clinvar	161
missense	6 clinvar	32 clinvar	402 clinvar	58 clinvar	3 clinvar	501
nonsense	25 clinvar	10 clinvar	23 clinvar			58
start loss	1 clinvar	1 clinvar				2
frameshift	17 clinvar	16 clinvar	1 clinvar			34
splice donor/acceptor (+/-2bp)	8 clinvar	23 clinvar	53 clinvar			84
Total	57	82	530	158	13	840

Highest pathogenic variant AF is 0.00005791135

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000292.3	RefSeq	NP_000283.1	33	MANE Select
ENST00000379942.5	Ensembl	ENSP00000369274.4	33	MANE Select
NM_001440800.1	RefSeq	NP_001427729.1	32	Standard
NM_001440801.1	RefSeq	NP_001427730.1	31	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glucagon signaling pathway - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)
Insulin signaling pathway - Homo sapiens (human)
Type II diabetes mellitus
Glycogen Metabolism

Biological Process

carbohydrate metabolic process
glycogen metabolic process
generation of precursor metabolites and energy
cellular protein modification process
protein phosphorylation

Molecular Function

phosphorylase kinase activity
protein binding
calmodulin binding

Cellular Component

cytosol
plasma membrane
phosphorylase kinase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379942
Coding exons: 33
Length: 92299
Individuals with no LoFs: 125736
Homozygous LoFs: 3
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.82	404	521	0.775	0.0000446	8091
Missense (PolyPhen)		91	175.63	0.51815		2743
Synonymous	-2.04	257	219	1.18	0.0000207	2414
Loss of Function	5.01	11	48.8	0.225	0.00000354	802

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00014	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.000079	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The alpha chain may bind calmodulin.;
Disease: DISEASE: Glycogen storage disease 9A (GSD9A) [MIM:306000]: A metabolic disorder resulting in a mild liver glycogenosis with clinical symptoms that include hepatomegaly, growth retardation, muscle weakness, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolemia, hypertriglyceridemia, and fasting hyperketosis. Two subtypes are known: type 1 or classic type with no phosphorylase kinase activity in liver or erythrocytes, and type 2 or variant type with no phosphorylase kinase activity in liver, but normal activity in erythrocytes. Unlike other glycogenosis diseases, glycogen storage disease type 9A is generally a benign condition. Patients improve with age and are often asymptomatic as adults. Accurate diagnosis is therefore also of prognostic interest. {ECO:0000269|PubMed:10330341, ECO:0000269|PubMed:17689125, ECO:0000269|PubMed:7549948, ECO:0000269|PubMed:7847371, ECO:0000269|PubMed:8733133, ECO:0000269|PubMed:8733134, ECO:0000269|PubMed:9600238}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.392

Intolerance Scores

LoFtool: 0.0519
RVIS EVS: -0.57
RVIS percentile EVS: 19.05

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.625

Gene Damage Prediction

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