Human Gene Module / Chromosome 4 / CAMK2D

CAMK2Dcalcium/calmodulin dependent protein kinase II delta

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
1 / 3
Rare Variants / Common Variants
9 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
4q26
Associated Disorders
-
Relevance to Autism

Rigter et al., 2024 described a cohort of eight individuals with heterozygous CAMK2D variants presenting with a developmental disorder consisting of developmental delay or intellectual disability characterized by speech and motor delay, dilated cardiomyopathy, dysmorphic features, variable skeletal malformations, and behavioral anomalies, including autism spectrum disorder in four individuals; functional assessment of CAMK2D missense variants identified in affected individuals in this report demonstrated either loss-of-function or gain-of-function effects. A maternally-inherited loss-of-function variant in this gene had previously been observed in an ASD proband from a multiplex family from the AGRE cohort in Cirnigliaro et al., 2023.

Molecular Function

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 delta chain.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CAMK2D (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Cirnigliaro M et al. (2023) Yes -
2 Primary - Pomme M F Rigter et al. (2024) No ASD, ADHD, epilepsy/seizures
3 Support - Noor Smal et al. () No -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.275+1G>T - splice_site_variant De novo - Simplex 38965372 Noor Smal et al. ()
c.275+1G>T - splice_site_variant De novo - Simplex 38272033 Pomme M F Rigter et al. (2024)
c.236G>A p.Ser79Asn missense_variant De novo - Simplex 38272033 Pomme M F Rigter et al. (2024)
c.416C>T p.Pro139Leu missense_variant De novo - Simplex 38272033 Pomme M F Rigter et al. (2024)
c.628G>A p.Gly210Arg missense_variant De novo - Simplex 38272033 Pomme M F Rigter et al. (2024)
c.821A>C p.Gln274Pro missense_variant De novo - Simplex 38272033 Pomme M F Rigter et al. (2024)
c.873G>C p.Leu291Phe missense_variant De novo - Simplex 38272033 Pomme M F Rigter et al. (2024)
c.824G>A p.Arg275His missense_variant Unknown - Multiplex 38272033 Pomme M F Rigter et al. (2024)
c.1590G>A p.Trp530Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2024
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.4766385373349

Ranking 8470/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.016661668817136

Ranking 9581/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.83267445502399

Ranking 2922/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.36275343542519

Ranking 1866/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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