Human Gene Module / Chromosome 10 / CUL2

CUL2cullin 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
5 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
10p11.21
Associated Disorders
-
Relevance to Autism

Genome sequencing of 50 ASD probands and their unaffected parents from a Qatari cohort in Ben-Mahmoud et al., 2024 identified a de novo missense variant in the CUL2 gene that was not in gnomAD or the Qatar Genome Project and was predicted to be damaging with a CADD score of 29.9 in a male ASD proband. Additional de novo variants in the CUL2 gene, including a de novo loss-of-function variant and two de novo missense variants (one of which had a CADD score > 25), were previously reported in ASD probands from the MSSNG cohort, the SPARK cohort, and a Chinese ASD cohort (Yuen et al., 2015; Zhou et al., 2022; Trost et al., 2022; Wang et al., 2023).

Molecular Function

Enables ubiquitin ligase complex scaffold activity and ubiquitin protein ligase binding activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nucleoplasm. Part of Cul2-RING ubiquitin ligase complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CUL2 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
2 Support - Zhou X et al. (2022) Yes -
3 Support - Trost B et al. (2022) Yes -
4 Support - Wang J et al. (2023) Yes -
5 Primary - Afif Ben-Mahmoud et al. (2024) Yes DD, epilepsy/seizures
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1984C>T p.Pro662Ser missense_variant De novo - - 36368308 Trost B et al. (2022)
c.603+8G>A p.? splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2230G>A p.Val744Ile missense_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.2057G>T p.Arg686Leu missense_variant De novo - Simplex 39519104 Afif Ben-Mahmoud et al. (2024)
c.2228_2229insG p.Tyr743_Val744delinsTer stop_gained De novo - Simplex 37393044 Wang J et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.49860947252522

Ranking 2232/25841 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 0.9999984103976

Ranking 332/18225 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 0.93651187402939

Ranking 13220/18665 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 0.31607445465882

Ranking 2503/20870 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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