Human Gene Module / Chromosome 7 / GNB2

GNB2G protein subunit beta 2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
16 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
7q22.1
Associated Disorders
-
Relevance to Autism

Heterozygous mutations in the GNB2 gene are responsible for neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF; OMIM 619503) (Fukuda et al., 2020; Lansdon et al., 2021; Tan et al., 2021). Tan et al., 2021 identified 12 unrelated individuals with five de novo missense variants in the GNB2 gene; all individuals presented with developmental delay/intellectual disability with variable dysmorphism and extraneurologic features, and autistic behaviors were observed in six of these individuals, two of whom were diagnosed with autism spectrum disorder. A de novo missense variant in this gene was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Molecular Function

Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors.

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Reports related to GNB2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support - Fukuda T et al. (2020) No -
3 Support - Lansdon LA et al. (2021) No -
4 Primary - Tan NB et al. (2021) No ASD or autistic behavior, stereotypy
5 Support - Zhou X et al. (2022) Yes -
6 Support - Cirnigliaro M et al. (2023) Yes -
7 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.217G>A p.Ala73Thr missense_variant De novo - - 34183358 Tan NB et al. (2021)
c.229G>A p.Gly77Arg missense_variant De novo - - 34183358 Tan NB et al. (2021)
c.265A>G p.Lys89Glu missense_variant De novo - - 34183358 Tan NB et al. (2021)
c.266A>C p.Lys89Thr missense_variant De novo - - 34183358 Tan NB et al. (2021)
c.217G>A p.Ala73Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.803A>T p.Asn268Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.229G>A p.Gly77Arg missense_variant De novo - - 31698099 Fukuda T et al. (2020)
c.229G>T p.Gly77Trp missense_variant De novo - - 33971351 Lansdon LA et al. (2021)
c.217G>A p.Ala73Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.217G>A p.Ala73Thr missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.217G>A p.Ala73Thr missense_variant De novo - Simplex 34183358 Tan NB et al. (2021)
c.229G>A p.Gly77Arg missense_variant De novo - Simplex 34183358 Tan NB et al. (2021)
c.265A>G p.Lys89Glu missense_variant De novo - Simplex 34183358 Tan NB et al. (2021)
c.266A>C p.Lys89Thr missense_variant De novo - Simplex 34183358 Tan NB et al. (2021)
c.440C>T p.Ser147Leu missense_variant De novo - Simplex 34183358 Tan NB et al. (2021)
c.-89_-55del - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

Krishnan Probability Score

Score 0.61246222882569

Ranking 169/25841 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 0.98923943467318

Ranking 1828/18225 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 0.71078855815418

Ranking 1228/18665 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 0.028977159325268

Ranking 7814/20870 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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