Human Gene Module / Chromosome 6 / CDK19

CDK19cyclin dependent kinase 19

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
15 / 0
Aliases
CDK19, CDC2L6,  CDK11,  DEE87,  EIEE87,  bA346C16.3
Associated Syndromes
-
Chromosome Band
6q21
Associated Disorders
ASD
Relevance to Autism

A rare de novo missense variant in the CDK19 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, while a de novo nonsense variant in this gene was observed in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020. De novo missense variants in the CDK19 gene have been shown to cause a form of developmental and epileptic encephalopathy (DEE87; OMIM 618916); autism have been observed in a subset of affected individuals (Chung et al., 2020; Zarate et al., 2021). Furthermore, several recurrent CDK19 missense variants described in Chung et al., 2020 and Zarate et al., 2021 (p.Gly28Arg, p.Tyr32His, and p.Thr196Ala) were shown to exhibit significant functional effects in in vivo model systems.

Molecular Function

This gene encodes a protein that is one of the components of the Mediator co-activator complex. The Mediator complex is a multi-protein complex required for transcriptional activation by DNA binding transcription factors of genes transcribed by RNA polymerase II. The protein encoded by this gene is similar to cyclin-dependent kinase 8 which can also be a component of the Mediator complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CDK19 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
3 Support - Chung HL et al. (2020) No ASD
4 Recent recommendation - Zarate YA et al. (2021) No ASD or autistic features, stereotypy
5 Support - Yang S et al. (2021) No -
6 Support - Brea-Fernández AJ et al. (2022) No -
7 Support - Zhou X et al. (2022) Yes -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.838C>T p.Gln280Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.92C>A p.Thr31Asn missense_variant De novo - - 33568421 Yang S et al. (2021)
c.598C>T p.Arg200Trp missense_variant De novo - - 33495529 Zarate YA et al. (2021)
c.94T>C p.Tyr32His missense_variant De novo - Simplex 32330417 Chung HL et al. (2020)
c.82G>A p.Gly28Arg missense_variant De novo - Simplex 33495529 Zarate YA et al. (2021)
c.82G>C p.Gly28Arg missense_variant De novo - Simplex 33495529 Zarate YA et al. (2021)
c.83G>C p.Gly28Ala missense_variant De novo - Simplex 33495529 Zarate YA et al. (2021)
c.94T>C p.Tyr32His missense_variant De novo - Simplex 33495529 Zarate YA et al. (2021)
c.95A>G p.Tyr32Cys missense_variant De novo - Simplex 33495529 Zarate YA et al. (2021)
c.586A>G p.Thr196Ala missense_variant De novo - Simplex 32330417 Chung HL et al. (2020)
c.589T>C p.Phe197Leu missense_variant De novo - Simplex 33495529 Zarate YA et al. (2021)
c.594G>C p.Trp198Cys missense_variant De novo - Simplex 33495529 Zarate YA et al. (2021)
c.1175C>G p.Pro392Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.168_173del p.Thr57_Gly58del inframe_deletion De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.863_864insGCCTCATAAAGTACA p.Tyr288delinsTer stop_gained De novo - - 31981491 Satterstrom FK et al. (2020)
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."

4/1/2022
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.49763489840821

Ranking 2353/25841 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 0.99801709140742

Ranking 1254/18225 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 0.93490698978954

Ranking 12712/18665 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 0.50775818821433

Ranking 469/20870 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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