Human Gene Module / Chromosome 8 / CNGB3

CNGB3cyclic nucleotide gated channel beta 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
13 / 0
Aliases
CNGB3, ACHM1
Associated Syndromes
-
Chromosome Band
8q21.3
Associated Disorders
-
Relevance to Autism

A de novo nonsense variant in the CNGB3 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04).

Molecular Function

This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CNGB3 (6 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 Recent Recommendation Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support - Woodbury-Smith M et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.494-8dup - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.1717G>A p.Gly573Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2348C>A p.Ser783Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.1504C>T p.Leu502%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1591C>A p.Gln531Lys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.231T>C p.Asn77%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2171A>T p.Glu724Val missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.1946A>G p.Lys649Arg missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2086C>T p.Arg696Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2086C>T p.Arg696Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2410A>T p.Lys804Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.894_898del p.Lys299SerfsTer11 frameshift_variant Familial Paternal Simplex 31398340 Ruzzo EK , et al. (2019)
c.2086C>T p.Arg696Ter stop_gained Familial Paternal Multiplex (monozygotic twins) 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo nonsense variant in the CNGB3 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04).

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 CNGB3 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo nonsense variant in the CNGB3 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04).

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

Decreased from 4 to 4

Description

A de novo nonsense variant in the CNGB3 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2017
icon
4

Increased from to 4

Description

A de novo nonsense variant in the CNGB3 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04).

Krishnan Probability Score

Score 0.50356895832119

Ranking 1940/25841 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 8.8646359547629E-11

Ranking 16945/18225 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 0.50504931042295

Ranking 459/18665 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 0.001627225513558

Ranking 8646/20870 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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