BCKDK

Chr 16AR

branched chain keto acid dehydrogenase kinase

Also known as: BCKDKD, BDK

NCBI Gene: 10295 ENSG00000103507 UniProt: O14874 OMIM: 614901

The protein phosphorylates and inactivates the branched-chain alpha-ketoacid dehydrogenase complex in the mitochondrial matrix, regulating the catabolism of valine, leucine, and isoleucine. Mutations cause branched-chain keto acid dehydrogenase kinase deficiency through an autosomal recessive inheritance pattern. The pathogenic mechanism involves dominant-negative effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Branched-chain keto acid dehydrogenase kinase deficiencyMIM #614923

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · branched-chain keto acid dehydrogenase kinase deficiency · AR · ClinGen 2019

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.87

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.00

OE 0.51 (0.31–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.64Z-score

OE missense 0.73 (0.65–0.82)

209 obs / 287.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.31–0.87)

0≤0.351.4

Missense OE?0.73 (0.65–0.82)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 10 / 19.6Missense obs/exp: 209 / 287.1Syn Z: -0.18

Background carrier burden — how many people carry a rare variant somewhere in BCKDK?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 84

624 rare PASS variants

Rare truncating (LoF)

1 in 2,000

110 rare PASS variants

Rare synonymous (reference)

1 in 210

294 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BCKDK. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 94	1 in 2,300
South Asian	~43k	1 in 100	1 in 3,000
Remaining (unassigned)	~30k	1 in 75	1 in 2,000
European (Finnish)	~27k	1 in 290	≈ 1 in 8,300
Admixed American	~22k	1 in 94	1 in 1,100
African / African American	~21k	1 in 110	1 in 2,400
East Asian	~20k	1 in 110	1 in 960
Ashkenazi Jewish	~13k	1 in 270	1 in 640
Middle Eastern	~2,884	1 in 99	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓