PDK2

protein-coding

pyruvate dehydrogenase kinase 2

Gene summary

This gene encodes a member of the pyruvate dehydrogenase kinase family. The encoded protein phosphorylates pyruvate dehydrogenase, down-regulating the activity of the mitochondrial pyruvate dehydrogenase complex. Overexpression of this gene may play a role in both cancer and diabetes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

MANE transcript

NM_002611.5

Inheritance

—

ClinVar variants

U:40B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr17:50,094,737-50,112,152

External References & Databases

Ensembl (ENSG00000005882)

Transcript & Mutation Effects

hg38 • Region Span ~17.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDK2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 34

not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002611.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar		2 clinvar	4
missense			35 clinvar	1 clinvar		36
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	40	1	2	43

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002611.5	RefSeq	NP_002602.2	11	MANE Select
ENST00000503176.6	Ensembl	ENSP00000420927.1	11	MANE Select
NM_001199898.2	RefSeq	NP_001186827.1	10	Standard
NM_001199899.2	RefSeq	NP_001186828.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
mtor signaling pathway
regulation of eif-4e and p70s6 kinase
pten dependent cell cycle arrest and apoptosis
skeletal muscle hypertrophy is regulated via akt-mtor pathway

Biological Process

glucose metabolic process
regulation of gluconeogenesis
protein phosphorylation
regulation of pH
insulin receptor signaling pathway

Molecular Function

protein kinase activity
pyruvate dehydrogenase (acetyl-transferring) kinase activity
ATP binding
protein homodimerization activity

Cellular Component

nucleoplasm
mitochondrion
mitochondrial matrix
cytosol
mitochondrial pyruvate dehydrogenase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000503176
Coding exons: 11
Length: 17416
Individuals with no LoFs: 125719
Homozygous LoFs: 1
Heterozygous LoFs: 28
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.05	155	245	0.632	0.0000142	2667
Missense (PolyPhen)		59	95.652	0.61682		1043
Synonymous	-0.958	116	104	1.12	0.00000691	773
Loss of Function	1.85	12	21.2	0.567	0.00000115	230

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00020	0.00020	rare
Other	0.00066	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis. {ECO:0000269|PubMed:17222789, ECO:0000269|PubMed:19833728, ECO:0000269|PubMed:21283817, ECO:0000269|PubMed:22123926, ECO:0000269|PubMed:7499431, ECO:0000269|PubMed:9787110}.;

Recessive Scores

pRec: 0.172

Intolerance Scores

LoFtool: 0.575
RVIS EVS: -0.23
RVIS percentile EVS: 37.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.978

Gene Damage Prediction

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