CAMK2A

protein-coding

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

Gene summary

The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. This calcium calmodulin-dependent protein kinase is composed of four different chains: alpha, beta, gamma, and delta. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2018]

Previous symbols:

CAMKA

MANE transcript

NM_015981.4

Inheritance

AD, AR

ClinVar variants

P:37U:99B:34

Top phenotype

Mental retardation, autosomal dominant, 53; Mental retardation, autosomal recessive, 63

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr5:150,219,491-150,290,093

External References & Databases

Ensembl (ENSG00000070808)

Transcript & Mutation Effects

hg38 • Region Span ~70.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CAMK2A* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2017 (Kury et al., PMID: 29100089). Variable clinical manifestations, including global developmental delay, mild to severe intellectual disability, delayed or absent speech, seizures, dysmorphic features, and behavioural and psychiatric manifestations such as autism spectrum disorder, aggressive behaviour, and hyperactivity characterise probands with *CAMK2A*-related complex neurodevelopmental disorder. Sixteen variants (missense, in-frame indel, nonsense and splice-site) that have been reported in 18 probands in three publications (PMIDs: 29100089, 29560374, 37510258) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is thought to be both gain-of-function and loss-of-function (PMIDs: 29100089, 29560374). Overall, functional and clinical data suggest that gain-of-function variants that affect the autoregulatory domain correlate with a more severe phenotype. This gene-disease relationship is also supported by in vitro phosphorylation of the *CAMK2A* protein and its impact on neuron migration, with both increased or decreased phosphorylation leading to reduced neuron migration (PMID: 29100089). In summary, there is definitive evidence supporting the relationship between *CAMK2A* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 15, 2024 (SOP Version 11).

intellectual developmental disorder, autosomal dominant 53STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030919

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 63LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0054861

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 63LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0054861

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 53MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030919

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 53STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030919

Submitter: G2P

Clinical Genomic Database (CGD)

Mental retardation, autosomal dominant, 53; Mental retardation, autosomal recessive, 63AD/AR

Manifestation: Craniofacial; 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: 28130356; 29100089; 29784083

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAMK2A variants in ClinVar

10 Conditions Cataloged

not providedTotal: 106

Intellectual developmental disorder, autosomal dominant 53Total: 37

Inborn genetic diseasesTotal: 29

not specifiedTotal: 28

CAMK2A-related disorderTotal: 13

Intellectual disabilityTotal: 11

Intellectual developmental disorder, autosomal recessive 63Total: 4

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015981.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	24 clinvar	1 clinvar	31
missense	8 clinvar	15 clinvar	82 clinvar	9 clinvar		114
nonsense	3 clinvar	4 clinvar	2 clinvar			9
start loss						0
frameshift		2 clinvar	4 clinvar			6
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	5 clinvar			10
Total	13	24	99	33	1	170

Highest pathogenic variant AF is 0.000006574795

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015981.4	RefSeq	NP_057065.2	19	MANE Select
ENST00000671881.1	Ensembl	ENSP00000500386.1	19	MANE Select
NM_001363989.1	RefSeq	NP_001350918.1	19	Standard
NM_001363990.1	RefSeq	NP_001350919.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
camk2a	Danio rerio	Structure: Mauthner neuron Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

camk2a

Danio rerio

Structure: Mauthner neuron

Quality: process quality

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

G1/S transition of mitotic cell cycle
MAPK cascade
response to ischemia
protein phosphorylation
calcium ion transport

Molecular Function

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

Cellular Component

nucleus
nucleoplasm
cytoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398376
Coding exons: 19
Length: 70801
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125692
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.68	72	300	0.240	0.0000187	3181
Missense (PolyPhen)		27	154.3	0.17499		1622
Synonymous	0.823	113	125	0.906	0.00000839	933
Loss of Function	4.98	4	36.5	0.110	0.00000198	389

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

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 synaptic plasticity, neurotransmitter release and long-term potentiation. 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:28130356). Also regulates the migration of developing neurons (PubMed:29100089). Phosphorylates the transcription factor FOXO3 to activate its transcriptional activity (PubMed:23805378). {ECO:0000250|UniProtKB:P11275, ECO:0000269|PubMed:23805378, ECO:0000269|PubMed:28130356, ECO:0000269|PubMed:29100089}.;
Disease: DISEASE: Mental retardation, autosomal dominant 53 (MRD53) [MIM:617798]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:25533962, ECO:0000269|PubMed:28130356, ECO:0000269|PubMed:29100089}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.388

Intolerance Scores

LoFtool: 0.165
RVIS EVS: -0.54
RVIS percentile EVS: 20.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.977

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low