GeneBe

CAMK2G

protein-coding

calcium/calmodulin dependent protein kinase II gamma, the group of Calmodulin dependent protein kinases

Gene summary

The product of this gene is one of the four subunits of an enzyme which belongs to the serine/threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. In mammalian cells the enzyme is composed of four different chains: alpha, beta, gamma, and delta. The product of this gene is a gamma chain. Many alternatively spliced transcripts encoding different isoforms have been described but the full-length nature of all the variants has not been determined.[provided by RefSeq, Mar 2011]

Previous symbols:
  • CAMKG

MANE transcript

NM_001367534.1

Inheritance

AD, AR

ClinVar variants

P:5U:108B:20

Top phenotype

Intellectual developmental disorder, autosomal dominant 59

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr10:73,812,501-73,874,591

External References & Databases

Ensembl (ENSG00000148660)NCBI Gene (818)OMIM (602123)HGNC:1463GenCCUniProt (Q13555)AlphaFoldClinVar (CAMK2G)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~62.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder 59LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032795

Submitter: ClinGen

The *CAMK2G* gene is located on chromosome 10 at 10q22.2 and encodes the calcium/calmodulin dependent protein kinase II gamma protein which is associated with calcium transport in the sarcoplasmic reticulum in skeletal muscle and may be involved in dendritic and neuronal functioning. *CAMK2G* was first reported in relation to autosomal dominant syndromic intellectual disability in 2012 (de Ligt et al., PMID 23033978). Two missense variants have been identified in three unrelated heterozygous individuals with de novo inheritance and similar phenotypic presentations (PMIDs: 23033978, 30184290, 35599849). Six additional mutations have been reported in association with intellectual disability in ClinVar (PMID 24234437). Multiple functional studies were done to assess the impact of the Arg292Pro variant, found in two cases, and the results showed an effect on protein stability and nuclear localization (PMID 30184290). A cell culture model using mouse primary hippocampal neurons showed substantial alteration of neuronal morphology in mice transfected with shRNA directed against Camk2g when compared with controls (PMID 30184290). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders Gene Curation Expert Panel on January 6th, 2021. It was reevaluated on October 11th, 2024. As a result of this reevaluation, the classification did not change.

intellectual developmental disorder 59LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032795

Submitter: Illumina

genetic developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Ambry Genetics

intellectual developmental disorder 59STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032795

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder 59STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032795

Submitter: G2P

intellectual developmental disorder 59LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032795

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 59AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23033978; 30184290Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAMK2G variants in ClinVar

10 Conditions Cataloged
not specifiedTotal: 61
not providedTotal: 48
Intellectual developmental disorder 59Total: 21
CAMK2G-related disorderTotal: 11
CAMK2G-related syndromic intellectual disabilityTotal: 1
Neurodevelopmental disorderTotal: 1
AutismTotal: 1
Generalized hypotoniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001367534.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
12
clinvar
3
clinvar
 16
missense
4
clinvar
95
clinvar
5
clinvar
 104
nonsense
2
clinvar
 2
start loss
0
frameshift
1
clinvar
2
clinvar
 3
splice donor/acceptor (+/-2bp)
8
clinvar
 8
Total05108173133

Highest pathogenic variant AF is 6.8551935e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 303 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001367534.1RefSeqNP_001354463.122MANE Select
ENST00000423381.6EnsemblENSP00000410298.322MANE Select
NM_001204492.2RefSeqNP_001191421.120Standard
NM_001222.4RefSeqNP_001213.218Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
camk2g2Danio rerio

Structure: calmodulin-dependent protein kinase activity

Quality: decreased rate

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
  • Aldosterone synthesis and secretion - Homo sapiens (human)
  • Oxytocin signaling pathway - Homo sapiens (human)
  • Long-term potentiation - Homo sapiens (human)
  • Neurotrophin signaling pathway - Homo sapiens (human)

Biological Process

  • MAPK cascade
  • protein dephosphorylation
  • nervous system development
  • regulation of skeletal muscle adaptation
  • insulin secretion

Molecular Function

  • protein serine/threonine kinase activity
  • calmodulin-dependent protein kinase activity
  • calcium-dependent protein serine/threonine phosphatase activity
  • Ras guanyl-nucleotide exchange factor activity
  • protein binding

Cellular Component

  • nucleoplasm
  • cytoplasm
  • cytosol
  • plasma membrane
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000322680
Coding exons
20
Length
62085
Individuals with no LoFs
125739
Homozygous LoFs
0
Heterozygous LoFs
9
Defined
125748
p
0.0000358
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.801453430.4220.00002113646
Missense (PolyPhen)67216.980.308782303
Synonymous0.9231181310.8980.000008271054
Loss of Function5.11437.90.1050.00000207408

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000440.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in sarcoplasmic reticulum Ca(2+) transport in skeletal muscle and may function in dendritic spine and synapse formation and neuronal plasticity. In slow- twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of the ryanodine receptor-coupling factor triadin. In neurons, may participate in the promotion of dendritic spine and synapse formation and maintenance of synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. {ECO:0000269|PubMed:16690701}.;

Recessive Scores

pRec
0.609

Intolerance Scores

LoFtool
0.466
RVIS EVS
-0.56
RVIS percentile EVS
19.31

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.921

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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