ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
Evidence for haploinsufficiency phenotype
PubMed ID Description
29100089 A report by Kury et al (2017) describes 10 de novo variants in the CAMK2B gene in unrelated individuals with intellectual disability who underwent exome sequencing. Of those 10 variants, one is an early nonsense variant and two are canonical slice site substitutions.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 mutations had increased activity and showed more severe migration deficits. Common findings shared across most individuals with de novo CAMK2B variants includes: mild to severe intellectual disability, delayed speech, hypotonia, facial dysmorphism, and digestive system, growth, and visual abnormalities.

Haploinsufficiency phenotype comments:

One publication (Kury et al) identified >3 de novo CAMK2B variants that likely result in loss of function, and several other de novo missense variants. However, functional studies supported both loss of function and gain of function disease mechanisms. Due to the fact that there is only one relevant publication to date and the fact that there is evidence for both gain of function and loss of function effects, we have scored the haploinsufficiency score as 2 instead of 3. 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.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity