CDK5

Chr 7AR

cyclin dependent kinase 5

Also known as: LIS7, PSSALRE

NCBI Gene: 1020 ENSG00000164885 UniProt: Q00535

This gene encodes a proline-directed serine/threonine kinase that is a member of the cyclin-dependent kinase family of proteins. Unlike other members of the family, the protein encoded by this gene does not directly control cell cycle regulation. Instead the protein, which is predominantly expressed at high levels in mammalian postmitotic central nervous system neurons, functions in diverse processes such as synaptic plasticity and neuronal migration through phosphorylation of proteins required for cytoskeletal organization, endocytosis and exocytosis, and apoptosis. In humans, an allelic variant of the gene that results in undetectable levels of the protein has been associated with lethal autosomal recessive lissencephaly-7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

Primary Disease Associations & Inheritance

?Lissencephaly 7 with cerebellar hypoplasiaMIM #616342

UniProtLissencephaly 7, with cerebellar hypoplasia

155

ClinVar variants

Pathogenic / LP

0.14

pLI score

Active trials

Clinical Summary— CDK5

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Gene-Disease Validity (ClinGen)

lissencephaly with cerebellar hypoplasia · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

75 Pathogenic / Likely Pathogenic· 20 VUS of 155 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.56LOEUF

pLI 0.139

Z-score 2.94

OE 0.27 (0.14–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.07Z-score

OE missense 0.33 (0.27–0.42)

56 obs / 167.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.27 (0.14–0.56)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.33 (0.27–0.42)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00

0≤1.21.6

LoF obs/exp: 5 / 18.7Missense obs/exp: 56 / 167.8Syn Z: 0.03