PHKG2

protein-coding

phosphorylase kinase catalytic subunit gamma 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, encoded by two different genes. 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, and the hepatic isoform is encoded by this gene. 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 9C, also known as autosomal liver glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

MANE transcript

NM_000294.3

Inheritance

ClinVar variants

P:60U:111B:146

Top phenotype

Glycogen storage disease IXc

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr16:30,748,293-30,761,176

External References & Databases

Ensembl (ENSG00000156873)

Transcript & Mutation Effects

hg38 • Region Span ~12.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease IXcSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013091

Submitter: Genomics England PanelApp

glycogen storage disease IXcSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013091

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease due to liver phosphorylase kinase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020693

Submitter: Orphanet

glycogen storage disease IXcDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013091

Submitter: ClinGen

*PHKG2* was first reported in relation to autosomal recessive glycogen storage disease (GSD) IXc in 1996 (Maichele et al., PMID: 8896567). *PHKG2* is the hepatic and testis isoform of the phosphorylase b kinase (PhK) gamma subunit, which activates glycogen phosphorylase. Since glycogen phosphorylase activation is necessary for glycogen breakdown, *PHKG2* dysfunction leads to GSD IXc, an inborn error of glycogenolysis. Patients with GSD IXc usually present with elevated transaminases, hypertriglyceridemia, hepatomegaly, and fasting hypoglycemia. Clinical manifestations also include hypercholesterolemia, hypotonia, and growth and/or developmental delay (PMID: 34876562). After childhood, symptoms can improve with proper management. However, it is possible for patients to develop severe hepatic phenotypes such as cirrhosis or fibrosis (PMID: 32697758). There are currently no alternative diseases in the literature associated with *PHKG2*. 14 variants (5 missense, 2 in-frame indel, 3 nonsense, 4 frameshift) that have been reported in 10 probands in 9 publications (PMID: 6962066, 8896567, 9384616, 35549678, 34876562, 24389071, 32697758, 25266922, 21646031) are included in this curation. At least 7 patients were shown to have a variant that leads to significantly reduced or absent PhK activity (PMID: 6962066, 8896567, 9384616, 35549678, 24389071, 25266922, 21646031). This disease does not appear to disproportionately affect any specific population. Patients included in this curation have ancestry in Europe, East Asia, South Asia, Africa, and the Middle East. One variant of interest (c.643G>A [p.Asp215Asn]) seen in one patient (PMID: 25266922) is interestingly the same variant observed in the rat model, as discussed below (PMID: 8896567). The mechanism of pathogenicity is known to be LOF. This gene-disease relationship is also supported by experimental evidence including biochemical assays and animal models (PMID: 34083142, 10487978, 30659246, 8896567). First, biochemical experiments demonstrating the function of *PHKG2* in glycogen metabolism are consistent with the phenotypes of elevated liver glycogen and hypoglycemia seen in patients (PMID: 10487978). Next, *PHKB* encodes a protein with a similar function to *PHKG2*, as *PHKB* is also a subunit (beta) of phosphorylase b kinase. *PHKB* is implicated in a similar disease, GSD IXb, and was classified as definitive by the General IEM GCEP (PMID: 30659246). GTEx analysis showed *PHKG2* highly expressed in the testis, but not more highly expressed in the liver compared to other tissues. Although this evidence was evaluated for expression evidence A, it was not scored due to lack of increased expression in hepatic tissues (PMID: 23715323). Maichele et al. published a rat model in 1996 with the p.D215N variant. This model organism demonstrated a variety of GSD-related phenotypes also seen in humans including hepatomegaly, elevated liver glycogen, and impaired glycogen mobilization during fasting (PMID: 8896567). Finally, Gibson et al. published a mouse model in 2021 developed through a targeted Phkg2 knockout. Similarly to the rat model from Maichele et al., these mice showed increased liver glycogen in addition to decreased liver PhK enzyme activity, increased liver body weight ratio (hepatomegaly), and early perisinusoidal liver fibrosis (PMID: 34083142). In summary, *PHKG2* is definitively associated with autosomal recessive glycogen storage disease IXc. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [03/08/2024] (SOP Version 10).

glycogen storage disease IXcSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013091

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Glycogen storage disease IXcAR

Manifestation: Biochemical; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Biochemical; Gastrointestinal

Rationale: In Liver PhK deficiency, dietary management can prevent and treat hypoglycemia during acute and stable periods; Specific hepatic surveillance is indicated in childhood; Other interventions have also been reported as beneficial

Refs: 6952760; 6962066; 8896567; 9245685; 9384616; 10905889; 12930917; 17689125; 21646031; 21634085; 24102521; 25266922; 33317799

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHKG2 variants in ClinVar

9 Conditions Cataloged

Glycogen storage disease IXcTotal: 334

Inborn genetic diseasesTotal: 68

not providedTotal: 45

not specifiedTotal: 31

PHKG2-related disorderTotal: 13

Glycogen phosphorylase kinase deficiencyTotal: 5

Glycogen storage diseaseTotal: 3

Glycogen storage disease type IXcTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000294.3. 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			1 clinvar	141 clinvar		142
missense	5 clinvar	12 clinvar	102 clinvar	5 clinvar		124
nonsense	13 clinvar	3 clinvar	2 clinvar			18
start loss						0
frameshift	12 clinvar	5 clinvar	2 clinvar			19
splice donor/acceptor (+/-2bp)	6 clinvar	4 clinvar	4 clinvar			14
Total	36	24	111	146	0	317

Highest pathogenic variant AF is 0.000101681464

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000294.3	RefSeq	NP_000285.1	9	MANE Select
ENST00000563588.6	Ensembl	ENSP00000455607.1	9	MANE Select
NM_001172432.2	RefSeq	NP_001165903.1	10	Standard
ENST00000328273.11	Ensembl	ENSP00000329968.7	9	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)
Glycogen Metabolism
Metabolism of carbohydrates

Biological Process

glycogen metabolic process
glycogen biosynthetic process
generation of precursor metabolites and energy
protein phosphorylation
positive regulation of glycogen catabolic process

Molecular Function

protein serine/threonine kinase activity
calmodulin-dependent protein kinase activity
phosphorylase kinase activity
protein binding
calmodulin binding

Cellular Component

cellular_component
cytosol
phosphorylase kinase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000563588
Coding exons: 9
Length: 12900
Individuals with no LoFs: 125702
Homozygous LoFs: 1
Heterozygous LoFs: 45
Defined: 125748
p: 0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.449	228	248	0.920	0.0000171	2624
Missense (PolyPhen)		94	103.77	0.90587		1078
Synonymous	-1.13	111	96.8	1.15	0.00000597	824
Loss of Function	2.76	8	22.0	0.364	0.00000135	215

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.0010	0.00088	notable
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000098	0.000098	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. May regulate glycogeneolysis in the testis. In vitro, phosphorylates PYGM (By similarity). {ECO:0000250, ECO:0000269|PubMed:10487978}.;
Disease: DISEASE: Glycogen storage disease 9C (GSD9C) [MIM:613027]: A metabolic disorder manifesting in infancy with hepatomegaly, growth retardation, hypotonia, liver dysfunction, and elevated plasma aminotransferases and lipids. These symptoms improve with age in most cases; however, some patients may develop hepatic fibrosis or cirrhosis. {ECO:0000269|PubMed:12930917, ECO:0000269|PubMed:8896567, ECO:0000269|PubMed:9245685}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.196

Intolerance Scores

LoFtool: 0.709
RVIS EVS: -0.71
RVIS percentile EVS: 14.5

Essentials

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

Gene Damage Prediction

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