BCKDK
protein-codingbranched chain keto acid dehydrogenase kinase
Gene summary
The branched-chain alpha-ketoacid dehydrogenase complex (BCKD) is an important regulator of the valine, leucine, and isoleucine catabolic pathways. The protein encoded by this gene is found in the mitochondrion, where it phosphorylates and inactivates BCKD. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013970
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013970
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013970
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013970
Submitter: ClinGen
BCKDK was first reported in relation to branched-chain keto acid dehydrogenase kinase deficiency, which is inherited in an autosomal recessive manner, in 2012 (Novarino et al, PMID 22956686). Evidence supporting this gene-disease relationship includes case-level and experimental data. Five unique variants (nonsense, frameshift, missense, and generation of a cryptic splice site) have been reported in in 8 individuals in 5 families (3 families each had 2 affected siblings) (Novarino et al, 2012, PMID 22956686; García-Cazorla et al, 2014, PMID 24449431). This gene-disease relationship is supported by the biochemical function of BCKDK, studies in fibroblasts from patients showing increased metabolism of branched chain alpha-keto acids, rescue of phosphorylation of E1-alpha in BCKDK-deficient fibroblasts upon expressing the wild type cDNA, a knock out mouse model (Joshi et al, 2006, PMID 16875466), and a natural rat model (Zigler et al, 2016, PMID 27472223). BCKDK negatively regulates the branched chain alpha-keto acid dehydrogenase (BCKD) complex by phosphorylating the E1-alpha subunit. As a result, the BCKD complex is constitutively active, resulting in the low levels of branched chain amino and alpha-keto acids observed in patients and animal models.
Inheritance Pattern: AR
Disease ID:MONDO:0013970
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Dermatologic; Neurologic
Intervention: Biochemical
Rationale: Individuals may present with features such as autism, microcephaly, and epilepsy, and dietary management (eg, with high protein diet and branch-chain amino acid supplementation) has been shown to result in laboratory-based and clinical improvement
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BCKDK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005881.4. 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 | 1 | 43 | 1 | 45 | ||
| missense | 2 | 3 | 88 | 4 | 97 | |
| nonsense | 2 | 4 | 1 | 7 | ||
| start loss | 0 | |||||
| frameshift | 3 | 3 | 6 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 4 | 6 | ||
| Total | 8 | 11 | 94 | 47 | 1 | 161 |
Highest pathogenic variant AF is 0.0000167285
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005872.2 | 11 | MANE Select | |
| Ensembl | ENSP00000219794.6 | 11 | MANE Select | |
| RefSeq | NP_001116429.1 | 10 | Standard | |
| RefSeq | NP_001258855.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Branched-chain amino acid catabolism
- Metabolism of amino acids and derivatives
- Metabolism
Biological Process
- protein phosphorylation
- cellular amino acid catabolic process
- branched-chain amino acid catabolic process
- phosphorylation
Molecular Function
- protein serine/threonine kinase activity
- protein binding
- ATP binding
- kinase activity
- [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity
Cellular Component
- mitochondrion
- mitochondrial matrix
- mitochondrial alpha-ketoglutarate dehydrogenase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394951
- Coding exons
- 11
- Length
- 6683
- Individuals with no LoFs
- 125718
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 29
- Defined
- 125747
- p
- 0.000115
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.64 | 209 | 287 | 0.728 | 0.0000204 | 2664 |
| Missense (PolyPhen) | 56 | 100.07 | 0.5596 | 957 | ||
| Synonymous | -0.181 | 124 | 121 | 1.02 | 0.00000865 | 868 |
| Loss of Function | 2.00 | 10 | 19.6 | 0.511 | 9.17e-7 | 226 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the key regulatory enzyme of the valine, leucine and isoleucine catabolic pathways. Key enzyme that regulate the activity state of the BCKD complex. {ECO:0000269|PubMed:24449431}.;
- Disease
- DISEASE: Branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD) [MIM:614923]: A metabolic disorder characterized by autism, epilepsy, intellectual disability, and reduced branched- chain amino acids. {ECO:0000269|PubMed:22956686, ECO:0000269|PubMed:24449431}. Note=The disease is caused by mutations affecting the gene represented in this entry. A diet enriched in branched amino acids (BCAAs) allows to normalize plasma BCAA levels. This suggests that it may be possible to treat patients with mutations in BCKDK with BCAA supplementation.;
Recessive Scores
- pRec
- 0.123
Intolerance Scores
- LoFtool
- 0.664
- RVIS EVS
- -0.54
- RVIS percentile EVS
- 20.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.929
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |