CAMK2B

Gene Facts

• HGNC Symbol: CAMK2B (HGNC:1461)
• HGNC Name: calcium/calmodulin dependent protein kinase II beta
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CAMKB
• Alias symbols: CAM2, CAMK2, CaMKIIβ
• %HI: 16.28
• pLI: 1
• LOEUF: 0.45
• Cytoband: 7p13
• Genomic Coordinates:

  GRCh37/hg19:	chr7:44256753-44365193
  GRCh38/hg38:	chr7:44217154-44326013

• MANE Select Transcript: NM_001220.5 ENST00000395749.7
• Function: Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic reticulum Ca(2+) transport in skeletal muscle (PubMed:16690701). In neurons, plays an essential structural role in the reorganization of the actin cytoskeleton during plasticity by binding and bundling actin filaments in a kinase- independent manner. This struct... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-27605
• ClinGen Curation ID: CCID:006782
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 01/25/2023

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• intellectual disability, autosomal dominant 54

HI Evidence

• PUBMED: 29100089
  Kury et al (2017) describe a multi-center collaborative study based on exome sequencing of 24 unrelated individuals with intellectual disability. In each participating center, clinical assessment was performed by at least one expert clinical geneticist. 10 de novo variants in the CAMK2B gene were identified, including an early nonsense variant (c.85C>T, p.Arg29∗) and two canonical slice site substitutions (c.820−1G>A and c.903+1G>A). The 2 splicing variants affect the canonical splice sequence and are predicted to lead to in-frame skipping of exon 11 according to bioinformatic predictions. It is unclear if these cause LOF. The authors examined the effects of both increasing and decreasing CAMK2B expression in mouse embryos and concluded that both resulted in neuronal migration defects. Functional studies were performed on the missense variants identified in the patients, and one (Lys301Glu) had reduced CAMK2B activity and resulted in neuronal migration disruption. However, the other missense variants had increased activity and showed more severe migration deficits. Common findings shared across most individuals with de novo CAMK2B variants include: mild to severe intellectual disability, delayed speech, hypotonia, facial dysmorphism, and digestive system, growth, and visual abnormalities.
• PUBMED: 33796307
  Heiman et al. (2021) report a 3yo female proband with complex focal seizures and global developmental delay, with a prominent delay in expressive speech. Whole Exome Sequencing performed at a clinical laboratory identified a maternally inherited c.85C>T (p.Arg29*) in the CAMK2A gene. The mother was reportedly healthy. The variant was subsequently detected in the proband's 8yo sister, who was reported to have speech difficulties, minimal balance issues, and mild myopia.
• PUBMED: 35519826
  Zhong et al. (2022) identified a de novo c.558del (p.Arg187Alafs*16) variant in a proband with esophageal atresia and tracheoesophageal fistulas, long gap, extra ribs, congenital scoliosis, and developmental delay. Variants were detected by trio whole genome sequencing using blood or saliva samples in a cohort of 185 individuals with esophageal atresia and tracheoesophageal fistulas.
• PUBMED: 35753512
  Similuk et al. (2022) identified a heterozygous c.85C>T (p.Arg29*) in a proband who underwent whole exome sequencing as part of a study of 1000 families with complex immune phenotypes. The 6yo proband was reported to have bronchial atresia, cough, delayed eruption of permanent teeth, eczema, fatigue, pain, poor appetite, recurrent ear infections, recurrent mycobacterial infections, seizure, and sinusitis.

• HI Evidence Comments: Due to the fact that there are relatively few cases reported to date with detailed clinical or family history information and the fact that there is evidence for both gain of function and loss of function effects, we have given a haploinsufficiency score of 1. The CAMK2B splice variant reported by Purcell et al (PMID 24463508, 2014) was not counted towards this scoring. Unlike the splice site variants reported by Kury et al, the variant reported by Purcell et al. is present in the gnomAD data set and corresponds to a donor site in only one of several transcripts; therefore, the probability that this is a disease-causing variant is reduced. A de novo frameshift variant was also reported by Bishop et al (PMID: 32574564, 2020) in an individual with orofacial clefting; however, additional phenotypic information was unavailable.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity