CDK19

Chr 6AD

cyclin dependent kinase 19

Also known as: CDC2L6, CDK11, DEE87, EIEE87, bA346C16.3

NCBI Gene: 23097 ENSG00000155111 UniProt: Q9BWU1 OMIM: 614720

CDK19 encodes a component of the Mediator co-activator complex that is required for transcriptional activation of genes by RNA polymerase II. Mutations cause developmental and epileptic encephalopathy 87 through an autosomal dominant inheritance pattern via loss-of-function mechanisms.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that is one of the components of the Mediator co-activator complex. The Mediator complex is a multi-protein complex required for transcriptional activation by DNA binding transcription factors of genes transcribed by RNA polymerase II. The protein encoded by this gene is similar to cyclin-dependent kinase 8 which can also be a component of the Mediator complex. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— CDK19

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 70 VUS of 113 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 4.82

OE 0.03 (0.01–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.56Z-score

OE missense 0.40 (0.35–0.47)

114 obs / 282.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.16)

0≤0.351.4

Missense OE?0.40 (0.35–0.47)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 1 / 29.0Missense obs/exp: 114 / 282.5Syn Z: 0.87

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCDK19-related intellectual disability and epileptic encephalopathyOTHERAD

This gene — mechanism propensity

0.3892th %ile

GOF

0.4085th %ile

LOF

0.79top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.16

DN1 literature citation

Literature Evidence

DNHowever, in vivo functional expression studies in Drosophila showed that the mutant protein localized normally to the perinuclear region in neurons, and that the mutation resulted in a loss-of-function effect acting in a dominant-negative manner.1

LOFQuantitative PCR of the CDK19 transcript from Epstein-Barr virus-transformed lymphoblastoid cell lines of the patient revealed ~50% reduction in the transcript (p = 0.02), suggesting haploinsufficiency of the gene.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

113 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic5

VUS70

Likely Benign14

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	4	1	0	5
VUS	5	61	4	0	70
Likely Benign	0	2	3	9	14
Benign	0	0	0	0	0
Conflicting	—				2
Total	5	71	8	9	95

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

18 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap CDK19 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →