BCKDK

branched chain keto acid dehydrogenase kinase

Basic information

Region (hg38): 16:31106106-31112791

Links

ENSG00000103507 ∙ NCBI:10295 ∙ OMIM:614901 ∙ HGNC:16902 ∙ Uniprot:O14874 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• branched-chain keto acid dehydrogenase kinase deficiency (Strong), mode of inheritance: AR
• branched-chain keto acid dehydrogenase kinase deficiency (Strong), mode of inheritance: AR
• branched-chain keto acid dehydrogenase kinase deficiency (Supportive), mode of inheritance: AR
• branched-chain keto acid dehydrogenase kinase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Branched-chain ketoacid dehydrogenase kinase deficiency	AR	Biochemical	Individuals may present with features such as autism and epilepsy, and though not definitely proven, there is strong evidence that dietary supplementation (eg, with branched chain amino acids) may be beneficial	Biochemical; Neurologic	22956686

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the BCKDK gene.

• Branched-chain keto acid dehydrogenase kinase deficiency (74 variants)
• not provided (45 variants)
• Inborn genetic diseases (16 variants)
• not specified (9 variants)
• BCKDK-related condition (2 variants)
• Maple syrup urine disease, mild variant (1 variants)
• Seizure (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the BCKDK gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	19	2	24
missense		1	57		1	59
nonsense	2	3				5
start loss						0
frameshift	1					1
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			5	6		11
non coding			3	8	4	15
Total	3	4	64	27	7

Highest pathogenic variant AF is 0.0000197

Variants in BCKDK

This is a list of pathogenic ClinVar variants found in the BCKDK region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-31109233-G-C		Branched-chain keto acid dehydrogenase kinase deficiency	Uncertain significance (Jan 15, 2020)
16-31109238-G-C		Branched-chain keto acid dehydrogenase kinase deficiency	Likely benign (Dec 03, 2021)
16-31109254-C-T		Branched-chain keto acid dehydrogenase kinase deficiency	Uncertain significance (Oct 24, 2021)
16-31109257-G-A		Branched-chain keto acid dehydrogenase kinase deficiency	Uncertain significance (Aug 04, 2023)
16-31109261-G-C			Uncertain significance (Oct 23, 2019)
16-31109268-TCCGCTCCGGCCCCTCCTGGGAC-T		Branched-chain keto acid dehydrogenase kinase deficiency	Pathogenic (Mar 16, 2021)
16-31109270-C-T			Uncertain significance (May 01, 2015)
16-31109277-G-A		Branched-chain keto acid dehydrogenase kinase deficiency	Likely benign (Jun 01, 2022)
16-31109289-A-T		Branched-chain keto acid dehydrogenase kinase deficiency	Likely benign (Aug 24, 2023)
16-31109301-G-C		Branched-chain keto acid dehydrogenase kinase deficiency	Likely benign (Aug 23, 2023)
16-31109302-C-T			Uncertain significance (Apr 01, 2019)
16-31109309-C-T		Branched-chain keto acid dehydrogenase kinase deficiency • Inborn genetic diseases	Uncertain significance (Jan 04, 2022)
16-31109340-C-G		Branched-chain keto acid dehydrogenase kinase deficiency	Uncertain significance (Aug 16, 2022)
16-31109343-G-A		Branched-chain keto acid dehydrogenase kinase deficiency • BCKDK-related disorder	Likely benign (Apr 24, 2023)
16-31109395-G-A		Inborn genetic diseases	Uncertain significance (Aug 12, 2022)
16-31109404-G-T		Branched-chain keto acid dehydrogenase kinase deficiency • not specified	Benign (Jan 08, 2024)
16-31109416-A-G		Branched-chain keto acid dehydrogenase kinase deficiency	Uncertain significance (Aug 31, 2021)
16-31109428-G-A		Branched-chain keto acid dehydrogenase kinase deficiency	Likely benign (Sep 12, 2022)
16-31109496-TC-T		Branched-chain keto acid dehydrogenase kinase deficiency	Likely benign (May 30, 2023)
16-31109500-TC-T		Branched-chain keto acid dehydrogenase kinase deficiency	Uncertain significance (Jan 15, 2022)
16-31109507-C-T		Branched-chain keto acid dehydrogenase kinase deficiency	Likely benign (Oct 04, 2022)
16-31109511-C-T		Inborn genetic diseases	Uncertain significance (Aug 12, 2021)
16-31109534-C-G		Branched-chain keto acid dehydrogenase kinase deficiency	Likely benign (Nov 27, 2023)
16-31109536-TG-T		Branched-chain keto acid dehydrogenase kinase deficiency	Pathogenic (Oct 19, 2012)
16-31109564-C-A			Uncertain significance (Jan 20, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
BCKDK	protein_coding	protein_coding	ENST00000394951	11	6683

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000566	0.974	125718	0	29	125747	0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.64	209	287	0.728	0.0000204	2664
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000178	0.000178
Ashkenazi Jewish	0.00	0.00
East Asian	0.000165	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000159	0.000158
Middle Eastern	0.000165	0.000163
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Branched-chain amino acid catabolism;Metabolism of amino acids and derivatives;Metabolism (Consensus)

Recessive Scores

• pRec: 0.123

Intolerance Scores

• loftool: 0.664
• rvis_EVS: -0.54
• rvis_percentile_EVS: 20.54

Haploinsufficiency Scores

• pHI: 0.193
• hipred: N
• hipred_score: 0.464
• ghis: 0.511

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.929

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Bckdk
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; renal/urinary system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype; muscle phenotype

Gene ontology

• Biological process: protein phosphorylation;cellular amino acid catabolic process;branched-chain amino acid catabolic process;phosphorylation
• Cellular component: mitochondrion;mitochondrial matrix;mitochondrial alpha-ketoglutarate dehydrogenase complex
• Molecular function: protein serine/threonine kinase activity;protein binding;ATP binding;kinase activity;[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity