CAMK2B

protein-coding

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

Gene summary

The product of this gene 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 beta chain. It is possible that distinct isoforms of this chain have different cellular localizations and interact differently with calmodulin. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

Previous symbols:

CAMKB

MANE transcript

NM_001220.5

Inheritance

ClinVar variants

P:22U:339B:313

Top phenotype

Intellectual developmental disorder, autosomal dominant 54

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr7:44,210,019-44,334,577

External References & Databases

Ensembl (ENSG00000058404)

Transcript & Mutation Effects

hg38 • Region Span ~124.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic featuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014699

Submitter: Illumina

intellectual developmental disorder, autosomal dominant 54STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030920

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 54STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030920

Submitter: G2P

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 54AD

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

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAMK2B variants in ClinVar

20 Conditions Cataloged

not providedTotal: 865

Inborn genetic diseasesTotal: 81

not specifiedTotal: 81

Intellectual developmental disorder, autosomal dominant 54Total: 53

CAMK2B-related disorderTotal: 25

Intellectual disabilityTotal: 11

Autism spectrum disorderTotal: 2

Developmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001220.5. 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			10 clinvar	205 clinvar	5 clinvar	220
missense	5 clinvar	6 clinvar	258 clinvar	85 clinvar	10 clinvar	364
nonsense	1 clinvar	2 clinvar	9 clinvar			12
start loss						0
frameshift		1 clinvar	34 clinvar	5 clinvar		40
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	28 clinvar	3 clinvar		38
Total	8	14	339	298	15	674

Highest pathogenic variant AF is 0.0000061572478

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 256 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001220.5	RefSeq	NP_001211.3	23	MANE Select
ENST00000395749.7	Ensembl	ENSP00000379098.2	23	MANE Select
NM_001293170.2	RefSeq	NP_001280099.1	20	Standard
NM_172078.3	RefSeq	NP_742075.1	20	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
camk2b2	Danio rerio	Structure: pectoral fin Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

camk2b2

Danio rerio

Structure: pectoral fin

Quality: decreased length

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 phosphorylation
signal transduction
positive regulation of neuron projection development
regulation of skeletal muscle adaptation

Molecular Function

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

Cellular Component

nucleoplasm
cytoplasm
microtubule organizing center
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395749
Coding exons: 23
Length: 117428
Individuals with no LoFs: 125647
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125676
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.07	166	393	0.422	0.0000244	4277
Missense (PolyPhen)		40	158.73	0.25201		1627
Synonymous	0.219	160	164	0.978	0.0000114	1318
Loss of Function	4.65	8	39.6	0.202	0.00000207	453

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0016	0.0015	notable
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
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 dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic reticulum Ca(2+) transport in skeletal muscle. 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 structural function is required for correct targeting of CaMK2A, which acts downstream of NMDAR to promote dendritic spine and synapse formation and maintain synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. In developing hippocampal neurons, promotes arborization of the dendritic tree and in mature neurons, promotes dendritic remodeling. Also regulates the migration of developing neurons (PubMed:29100089). Participates in the modulation of skeletal muscle function in response to exercise. 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 triadin, a ryanodine receptor-coupling factor, and phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2. {ECO:0000269|PubMed:16690701, ECO:0000269|PubMed:29100089}.;
Disease: DISEASE: Mental retardation, autosomal dominant 54 (MRD54) [MIM:617799]: 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:29100089}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.299

Intolerance Scores

LoFtool: 0.575
RVIS EVS: -0.62
RVIS percentile EVS: 17.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.942

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium