Human Gene Module / Chromosome 5 / CYFIP2

CYFIP2cytoplasmic FMR1 interacting protein 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
20 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
5q33.3
Associated Disorders
-
Relevance to Autism

A de novo missense variant with an MPC score > 2 was identified in the CYFIP2 gene in a Korean ASD proband in Kim et al., 2024; this gene was subsequently classified as an ASD candidate gene in males following a combined TADA analysis consisting of the Korean ASD cohort described in Kim et al., 2024 in addition to the Simons Simplex Collection and the SPARK cohort. A de novo loss-of-function variant and seven de novo missense variants, including three missense variants with MPC scores>2, were previously identified in the CYFIP2 gene in ASD probands from the Autism Sequencing Consortium and the SPARK cohort (Satterstrom et al., 2020; Zhou et al., 2022; Fu et al., 2022; Trost et al., 2022). Heterozygous variants in CYFIP2 are also responsible for developmental and epileptic encephalopathy-65 (DEE65; OMIM 618008); Zweier et al., 2019 reported that, of the 12 individuals with de novo CYFIP2 variants who presented with developmental delay/intellectual disability and epilepsy in their cohort, one also presented with autism spectrum disorder while another presented with autistic features. Han et al., 2015 found that Cyfip2(+/-) mice exhibited behavioral phenotypes similar to Fmr1-null (Fmr1(-/y)) mice, an animal model of Fragile X syndrome.

Molecular Function

Predicted to enable small GTPase binding activity. Involved in several processes, including activation of cysteine-type endopeptidase activity; cell-cell adhesion; and regulation of postsynapse assembly. Located in perinuclear region of cytoplasm and synapse. Part of SCAR complex. Implicated in developmental and epileptic encephalopathy 65.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CYFIP2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Kihoon Han et al. (2015) No -
2 Support - Markus Zweier et al. (2019) No ASD or autistic features, ADHD
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Fu JM et al. (2022) Yes -
6 Support - Trost B et al. (2022) Yes -
7 Support - Liene Thys et al. (2024) No ASD, ID
8 Primary - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1900C>T p.Arg634Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1442C>T p.Ala481Val missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.1316G>A p.Arg439His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1363G>A p.Ala455Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2420C>T p.Thr807Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2506G>A p.Gly836Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2414G>A p.Arg805Gln missense_variant De novo - - 36368308 Trost B et al. (2022)
c.1992C>G p.Ile664Met missense_variant De novo - - 39213953 Liene Thys et al. (2024)
c.3669+1G>T p.? splice_site_variant De novo - - 30664714 Markus Zweier et al. (2019)
c.354G>A p.Glu118= synonymous_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.259C>T p.Arg87Cys missense_variant De novo - - 30664714 Markus Zweier et al. (2019)
c.1292C>T p.Ala431Val missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.322T>C p.Tyr108His missense_variant De novo - - 30664714 Markus Zweier et al. (2019)
c.1083C>T p.Ser361= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1363G>C p.Ala455Pro missense_variant De novo - - 30664714 Markus Zweier et al. (2019)
c.1992C>G p.Ile664Met missense_variant De novo - - 30664714 Markus Zweier et al. (2019)
c.1993G>A p.Glu665Lys missense_variant De novo - - 30664714 Markus Zweier et al. (2019)
c.2170G>C p.Asp724His missense_variant De novo - - 30664714 Markus Zweier et al. (2019)
c.2174A>G p.Gln725Arg missense_variant De novo - - 30664714 Markus Zweier et al. (2019)
c.3682G>A p.Val1228Met missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

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
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.55504621811759

Ranking 1348/25841 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 0.99999860259371

Ranking 322/18225 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 0.94756162634757

Ranking 17326/18665 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 0.4880349135074

Ranking 604/20870 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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