CAMK2B

Chr 7AD

calcium/calmodulin dependent protein kinase II beta

Also known as: CAM2, CAMK2, CAMKB, CaMKIIbeta, MRD54

NCBI Gene: 816 ENSG00000058404 UniProt: Q13554 OMIM: 607707

The protein encodes the beta subunit of calcium/calmodulin-dependent protein kinase II, a serine/threonine kinase essential for calcium signaling and synaptic plasticity at glutamatergic synapses. Mutations cause autosomal dominant intellectual developmental disorder, autosomal dominant 54. The low LOEUF score (0.364) indicates the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.361 OMIM phenotype

Clinical Summary— CAMK2B

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.74) — some intolerance to loss-of-function variants.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 239 VUS of 500 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.36LOEUF

pLI 0.739

Z-score 4.65

OE 0.20 (0.12–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

4.07Z-score

OE missense 0.42 (0.37–0.48)

166 obs / 393.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.20 (0.12–0.36)

0≤0.351.4

Missense OE0.42 (0.37–0.48)

0≤0.61.4

Synonymous OE0.98

0≤1.21.6

LoF obs/exp: 8 / 39.6Missense obs/exp: 166 / 393.1Syn Z: 0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCAMK2B-related intellectual disabilityLOFAD

0.5672th %ile

GOF

0.73top 25%

LOF

0.61top 25%

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

GOFprediction above median · 1 literature citation

LOF33% of P/LP variants are LoF · LOEUF 0.36

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNIn addition, overexpression or knockdown of wildtype CAMK2B resulted in clear neuronal migration defects. The variants appeared to act in a dominant-negative manner.PMID:29100089

GOFCAMK2B autophosphorylation at Thr287 is critical for autonomous (calcium-independent) function. E110K, P139L, and E237K (607707.0004) caused a significant increase in autophosphorylation at Thr287, consistent with a gain of function, whereas K301E (607706.0005) showed a significant reduction of Thr2PMID:29100089

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