CAMK2A |
- 1
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- CAMK2A (HGNC:1460) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- calcium/calmodulin dependent protein kinase II alpha
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- CAMKA
- Alias symbols
- KIAA0968, CaMKIINalpha, CaMKIIα
- %HI
- 5.97(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 1(Read more about gnomAD pLI score)
- LOEUF
- 0.25(Read more about gnomAD LOEUF score)
- Cytoband
- 5q32
- Genomic Coordinates
-
GRCh37/hg19: chr5:149599054-149669693 NCBI Ensembl UCSC GRCh38/hg38: chr5:150219491-150290130 NCBI Ensembl UCSC - MANE Select Transcript
- NM_015981.4 ENST00000671881.1 (Read more about MANE Select)
- Function
- Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in various processes, such as synaptic plasticity, neurotransmitter release and long-term potentiation (PubMed:14722083). Member of the NMDAR signaling complex in excitatory synapses, it regulates NMDAR-dependent potentiation of the AMPAR and therefore excitatory synaptic transmission (By similarity). Regulates dendritic spine development (PubMed:281303... (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Dosage ID:
ISCA-4187
Curation Status:
Complete
Issue Type:
Dosage Curation -
Gene
Haploinsufficiency:
Little Evidence for Haploinsufficiency
(1)
Triplosensitivity:
No Evidence for Triplosensitivity
(0)
Last Evaluated:
05/24/2023
Haploinsufficiency (HI) Score Details
HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency
(Disclaimer)
HI Disease:
- Mental retardation, autosomal dominant 53 Monarch
HI Evidence:
-
PUBMED:
29100089
Kury et al. (2017) describe 12 variants in CAMK2A identified in 14 individuals through clinical and research exome sequencing at 14 different sites. Of the 12 variants, 1 was a frameshift, 3 were splice site variants and 8 were missense. The frameshift variant (c.65del) occurred in exon 2 of 19 and was predicted to result in nonsense-mediated mRNA decay, suggesting a possible mechanism of halpoinsufficiency, but was of unknown inheritance (no paternal sample). Although the splice variants were predicted by in silico assessments to alter splicing, the predicted impacts did not suggest nonsense-mediated mRNA decay, and thus it is unclear if these variants would result in haploinsufficiency. CAMK2A-associated phenotypes in patients with potential loss-of-function variants included intellectual disability, behavioral abnormalities, and delayed speech with variable presentation of epilepsy, visual impairment, and mild dysmorphic features. In addition, the authors described 8 missense variants but noted that functional studies sometimes supported a loss-of-function mechanism, and other times, supported a gain-of-function mechanism.
-
PUBMED:
29560374
Akita et al. (2018) reported functional characterization of 3 de novo variants in CAMK2A identified through exome sequencing of a cohort of 976 individuals with intellectual disability, developmental delay, and epilepsy (previously reported in Kury et al., 2017). One variant (c.817-1G>A) occurred in a canonical splice site and was shown to cause skipping of exon 11 through a mini gene assay. Sequencing of the PCR products showed 3 aberrant transcripts for this splice variant; the most abundant transcript was an in-frame deletion of most of regulatory segment that mediates auto-inhibition, as well as 2 less abundant frameshift transcripts. The authors speculated that the in-frame deletion may exhibit constitutive activity. In addition, 2 missense variants, c.635C>A, p.(Pro212Gln) and c.704C>T, p.(Pro235Leu), occurred in the kinase domain of CAMK2A and were shown using a structural prediction model to adversely affect the interaction of the kinase domain and the segment that controls the auto-inhibition of its kinase activity. Immunoblot studies showed increased phosphorylation compared to wildtype. The authors suggested that these variants may disrupt the interaction between the kinase domain and regulatory segment, leading to decreased auto-inhibition and increased auto-phosphorylation, thereby increasing its Ca2+-independent activity. The authors indicate their “data suggest that the basal increase in CAMK2A activity is linked to neurodevelopmental disorders”.
-
PUBMED:
35143101
Sun et al. (2022) reported 1 de novo, frameshift variant, c.817-4_838del, p.(His 273Alafs*11), that overlaps the exon 11 splice acceptor site in CAMK2A. It was identified through whole genome sequencing of 100 patients with intellectual disability and/or global developmental delay. This variant occurred in exon 11 of 19 and its impact on protein production was not studied. Therefore, it is unclear if this variant would result in haploinsufficiency.
-
PUBMED:
24463508
Purcell et al. (2014) reported 1 nonsense variant, c.1219C>T, p.(Arg407*), in CAMK2A, identified through exome sequencing of 2,536 patients with schizophrenia. Inheritance was not reported. This variant occurred in exon 17 of 19 and its impact on protein production was not studied. Therefore, it is unclear if this variant would result in haploinsufficiency.
HI Evidence Comments:
Due to uncertainty regarding the true mechanism of disease, we are giving this gene a haploinsufficiency score of 1.
Other relevant PMIDs: 28191890, 28135719, 29784083, 23695276, 31785789
Triplosensitivity (TS) Score Details
TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
Genomic View
Select assembly:
(NC_000005.9)
(NC_000005.10)