Human Gene Module / Chromosome 7 / PRKAR1B

PRKAR1Bprotein kinase cAMP-dependent type I regulatory subunit beta

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
12 / 0
Aliases
PRKAR1B, PRKAR1
Associated Syndromes
Marbach-Schaaf neurodevelopmental syndrome, DD
Chromosome Band
7p22.3
Associated Disorders
ADHD
Relevance to Autism

A de novo nonsense variant in the PRKAR1B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while de novo missense variants in this gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify PRKAR1B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019). Marbach et al., 2021 characterized six individuals with PRKAR1B missense variants (five of which were confirmed de novo), all of whom were diagnosed with autism spectrum disorder and presented with global developmental delay, speech delay and/or regression, and dyspraxia/apraxia; functional analysis of PRKAR1B missense variants identified in this cohort demonstrated significantly reduced basal activity in cells transfected with mutant PRKAR1B compared to wild-type protein.

Molecular Function

The protein encoded by this gene is a regulatory subunit of cyclic AMP-dependent protein kinase A (PKA), which is involved in the signaling pathway of the second messenger cAMP. Two regulatory and two catalytic subunits form the PKA holoenzyme, disbands after cAMP binding. The holoenzyme is involved in many cellular events, including ion transport, metabolism, and transcription.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PRKAR1B (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Nonrandom occurrence of multiple de novo coding variants in a proband indicates the existence of an oligogenic model in autism Du Y , et al. (2019) Yes -
4 Recent Recommendation Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Recent Recommendation - Marbach F et al. (2021) Yes ADHD
6 Support - Marbach F et al. (2022) No ASD or autistic features, ADHD, ID
7 Support - Zhou X et al. (2022) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.638C>T p.Ala213Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.289C>T p.Arg97Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.1028G>A p.Gly343Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1003C>T p.Arg335Trp missense_variant De novo - - 35789103 Marbach F et al. (2022)
c.697C>T p.Arg233Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.586G>A p.Glu196Lys missense_variant De novo - Simplex 33833410 Marbach F et al. (2021)
c.1003C>T p.Arg335Trp missense_variant De novo - Simplex 33833410 Marbach F et al. (2021)
c.529G>C p.Val177Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.727C>T p.Arg243Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.727C>T p.Arg243Cys missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.500_501inv p.Gln167Leu missense_variant Unknown - Unknown 33833410 Marbach F et al. (2021)
c.1003C>T p.Arg335Trp missense_variant Unknown Not maternal - 35789103 Marbach F et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo nonsense variant in the PRKAR1B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while de novo missense variants in this gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify PRKAR1B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo nonsense variant in the PRKAR1B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while de novo missense variants in this gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify PRKAR1B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

4/1/2021
3
icon
3

Decreased from 3 to 3

Description

A de novo nonsense variant in the PRKAR1B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while de novo missense variants in this gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify PRKAR1B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Reports Added
[Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo nonsense variant in the PRKAR1B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while de novo missense variants in this gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify PRKAR1B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Reports Added
[New Scoring Scheme]
7/1/2019
icon
4

Increased from to 4

Description

A de novo nonsense variant in the PRKAR1B gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while de novo missense variants in this gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Two separate studies used TADA analysis to identify PRKAR1B as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Krishnan Probability Score

Score 0.56766871767152

Ranking 1163/25841 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 0.024757799563059

Ranking 9201/18225 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 0.13413437744112

Ranking 79/18665 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 0.28624030498214

Ranking 2932/20870 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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