Human Gene Module / Chromosome 11 / SHANK2

SHANK2SH3 and multiple ankyrin repeat domains 2

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
19 / 34
Rare Variants / Common Variants
81 / 1
Aliases
SHANK2, CORTBP1,  CTTNBP1,  ProSAP1,  SPANK-3,  SHANK2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Chromosome Band
11q13.3-q13.4
Associated Disorders
ASD, ID, EP, EPS
Relevance to Autism

Several studies have identified rare mutations in the SHANK2 gene in autistic and intellectually disabled individuals (Berkel et al., 2010; Pinto et al., 2010; Leblond et al., 2012; Sanders et al., 2012). A functional study analyzed three of the mutations previously found in individuals with ASD (L1008_P1009dup, T1127M and R462X). The mutations were found to have varying effects on protein localization, dendritic spine volume and branching in cultured neurons and even synaptic transmission and cognitive behavior in mice, with the R462X variant causing the most severe phenotypes (Berkel et al., 2012).

Molecular Function

Shank proteins contain multiple domains for protein-protein interactions and function as molecular scaffolds in the postsynaptic density (PSD).

Reports related to SHANK2 (33 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family. Boeckers TM , et al. (1999) No -
2 Highly Cited The Shank family of scaffold proteins. Sheng M and Kim E (2000) No -
3 Highly Cited The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal. Hwang JI , et al. (2005) No -
4 Recent Recommendation AnkyrinG is required to maintain axo-dendritic polarity in vivo. Sobotzik JM , et al. (2009) No -
5 Recent Recommendation BetaPix up-regulates Na? exchanger 3 through a Shank2-mediated protein-protein interaction. Lee JS , et al. (2010) No -
6 Recent Recommendation Activity induced changes in the distribution of Shanks at hippocampal synapses. Tao-Cheng JH , et al. (2010) No -
7 Primary Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Berkel S , et al. (2010) Yes MR
8 Support Functional impact of global rare copy number variation in autism spectrum disorders. Pinto D , et al. (2010) Yes -
9 Recent Recommendation Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology. Berkel S , et al. (2011) Yes ID
10 Support Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. Leblond CS , et al. (2012) Yes ID
11 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
12 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Rauch A , et al. (2012) No Epilepsy, ASD
13 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
14 Support Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangemen... Schluth-Bolard C , et al. (2013) No Autistic behavior
15 Support Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci. Chilian B , et al. (2013) No -
16 Negative Association Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. Liu Y , et al. (2013) Yes -
17 Recent Recommendation Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. Leblond CS , et al. (2014) Yes -
18 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Li J , et al. (2015) Yes -
19 Recent Recommendation Identification and functional characterization of rare SHANK2 variants in schizophrenia. Peykov S , et al. (2015) No -
20 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
21 Support Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness. Homann OR , et al. (2016) No -
22 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
23 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
24 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
25 Support A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders. de Sena Cortabitarte A , et al. (2018) No -
26 Positive Association Genetic association between SHANK2 polymorphisms and susceptibility to autism spectrum disorder. Bai Y , et al. (2018) Yes -
27 Support Eighteen-year-old man with autism, obsessive compulsive disorder and a SHANK2 variant presents with severe anorexia that responds to high-dose fluo... Lu ZA , et al. (2018) Yes -
28 Recent Recommendation Effect of the autism-associated lncRNA Shank2-AS on architecture and growth of neurons. Luo T , et al. (2018) No -
29 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
30 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c... Zhou WZ , et al. (2019) Yes -
31 Recent Recommendation SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons. Zaslavsky K , et al. (2019) Yes -
32 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort. Callaghan DB , et al. (2019) Yes -
33 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing. Aspromonte MC , et al. (2019) Yes -
Rare Variants   (81)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 23350639 Chilian B , et al. (2013)
- - copy_number_loss De novo NA - 20531469 Pinto D , et al. (2010)
- - translocation De novo NA - 25188300 Leblond CS , et al. (2014)
c.2142-5G>T - intron_variant - - - 20473310 Berkel S , et al. (2010)
- - copy_number_loss De novo NA - 20473310 Berkel S , et al. (2010)
c.1028+13G>A - intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1302+35G>A - intron_variant - - - 20473310 Berkel S , et al. (2010)
c.2142-15C>A - intron_variant - - - 20473310 Berkel S , et al. (2010)
c.2406-21C>T - intron_variant - - - 20473310 Berkel S , et al. (2010)
c.3843-12T>C - intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1148-109C>T - intron_variant - - - 20473310 Berkel S , et al. (2010)
c.913-8780C>T - intron_variant - - - 20473310 Berkel S , et al. (2010)
c.922-3220G>A - intron_variant - - - 20473310 Berkel S , et al. (2010)
- - copy_number_loss De novo NA - 22346768 Leblond CS , et al. (2012)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - nonsynonymous_variant Unknown - Unknown 25549968 Li J , et al. (2015)
- - copy_number_loss De novo NA Simplex 20473310 Berkel S , et al. (2010)
C>A p.Arg598Leu missense_variant - - - 22346768 Leblond CS , et al. (2012)
C>T p.Ser557Asn missense_variant - - - 22346768 Leblond CS , et al. (2012)
G>A p.Thr410Met missense_variant - - - 22346768 Leblond CS , et al. (2012)
c.316C>A p.Pro106Thr intron_variant - - - 20473310 Berkel S , et al. (2010)
c.587C>T p.Thr196Ile intron_variant - - - 20473310 Berkel S , et al. (2010)
C>T p.Met1717Ile missense_variant - - - 22346768 Leblond CS , et al. (2012)
- - inversion De novo NA Simplex 23315544 Schluth-Bolard C , et al. (2013)
c.1100G>A p.Gly367Asp intron_variant - - - 20473310 Berkel S , et al. (2010)
c.2269C>T p.Leu757Phe intron_variant - - - 20473310 Berkel S , et al. (2010)
c.2675G>C p.Arg892Pro intron_variant - - - 20473310 Berkel S , et al. (2010)
- - copy_number_loss De novo NA Simplex 25188300 Leblond CS , et al. (2014)
c.467A>G p.Lys156Arg missense_variant - - - 20473310 Berkel S , et al. (2010)
c.569G>A p.Arg190His missense_variant - - - 20473310 Berkel S , et al. (2010)
c.1201A>C p.Lys401Gln missense_variant - - - 20473310 Berkel S , et al. (2010)
c.1316G>A p.Cys439Tyr missense_variant - - - 20473310 Berkel S , et al. (2010)
c.1763A>G p.Tyr588Cys missense_variant - - - 20473310 Berkel S , et al. (2010)
C>A p.Gly488Val missense_variant Unknown - - 25560758 Peykov S , et al. (2015)
c.3471C>T p.His1157%3D missense_variant - - - 20473310 Berkel S , et al. (2010)
c.492G>A p.Leu164%3D synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.1243C>A p.His415Asn synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.1284G>A p.Gln428%3D synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.1903C>T p.Leu635Phe synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.1923G>A p.Glu641%3D synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.2823C>T p.Thr941%3D synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.2986C>T p.Arg996Trp synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.1178C>T p.Ala393Val missense_variant - - - 22346768 Leblond CS , et al. (2012)
c.*493dup - frameshift_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.3324C>T p.Asp1108%3D synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.3484G>A p.Gly1162Arg missense_variant - - - 22346768 Leblond CS , et al. (2012)
c.4126G>A p.Val1376Ile missense_variant - - - 22346768 Leblond CS , et al. (2012)
c.87C>G p.Tyr29Ter stop_gained De novo NA Simplex 30564305 Guo H , et al. (2018)
c.*1135_*1136del - frameshift_variant De novo NA - 30763456 Zhou WZ , et al. (2019)
c.1829C>A p.Pro610His missense_variant Unknown - - 25560758 Peykov S , et al. (2015)
c.1920A>G p.Ter640%3D missense_variant Unknown - - 25560758 Peykov S , et al. (2015)
c.2872C>A p.Arg958Ser missense_variant Unknown - - 25560758 Peykov S , et al. (2015)
c.3355C>A p.Pro1119Thr missense_variant Unknown - - 25560758 Peykov S , et al. (2015)
c.757C>T p.Arg253Ter stop_gained De novo NA Simplex 27525107 Yuen RK , et al. (2016)
c.1235G>A p.Arg412His stop_gained De novo NA Simplex 20473310 Berkel S , et al. (2010)
c.1727C>T p.Pro576Leu missense_variant Unknown - - 31209962 Aspromonte MC , et al. (2019)
c.2518C>T p.Pro840Ser missense_variant Familial Paternal - 29991577 Lu ZA , et al. (2018)
c.76G>A p.Asp26Asn missense_variant Familial Paternal - 20473310 Berkel S , et al. (2010)
c.622G>A p.Asp208Asn missense_variant Unknown - Simplex 20473310 Berkel S , et al. (2010)
c.*819A>T - missense_variant Familial Maternal Simplex 22346768 Leblond CS , et al. (2012)
c.132G>A p.Pro44%3D synonymous_variant De novo NA Simplex 23020937 Rauch A , et al. (2012)
c.1313C>T p.Thr438Met missense_variant Familial Maternal - 25560758 Peykov S , et al. (2015)
c.3380C>T p.Thr1127Ile missense_variant Familial Maternal - 20473310 Berkel S , et al. (2010)
c.3431C>T p.Ser1144Phe missense_variant Familial Maternal - 25560758 Peykov S , et al. (2015)
c.4673G>A p.Arg1558Gln missense_variant Familial Maternal - 25560758 Peykov S , et al. (2015)
c.4936C>A p.Leu1646Met missense_variant Familial Maternal - 25560758 Peykov S , et al. (2015)
- p.Ala578Val missense_variant Familial Maternal Multiplex 27001614 Homann OR , et al. (2016)
c.31G>A p.Glu11Lys missense_variant Unknown - Multiplex 31038196 Callaghan DB , et al. (2019)
c.3427G>A p.Ala1143Thr missense_variant De novo NA Simplex 28263302 C Yuen RK , et al. (2017)
c.359G>A p.Arg120Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
A>G p.Leu1722Pro missense_variant Familial Paternal Simplex 22346768 Leblond CS , et al. (2012)
C>T p.Gly1170Arg missense_variant Familial Maternal Simplex 22346768 Leblond CS , et al. (2012)
C>T p.Ala729Thr missense_variant Familial Maternal Multiplex 22346768 Leblond CS , et al. (2012)
c.692C>A p.Ser231Tyr missense_variant Familial Paternal Simplex 20473310 Berkel S , et al. (2010)
c.3142C>T p.Arg1048Trp missense_variant Familial Maternal Simplex 20473310 Berkel S , et al. (2010)
c.622C>T p.Pro208Ser missense_variant Familial Maternal Multiplex 20473310 Berkel S , et al. (2010)
c.2000G>T p.Gly667Val missense_variant Familial Paternal Simplex 22346768 Leblond CS , et al. (2012)
c.3899C>T p.Ala1300Val missense_variant Familial Maternal Multiplex 20473310 Berkel S , et al. (2010)
c.1494-1167_1494-1166insGT - frameshift_variant De novo NA Simplex 22495306 Sanders SJ , et al. (2012)
c.4642_4643insTCTCCA p.Ser1548delinsPheSerThr inframe_insertion Familial Maternal - 20473310 Berkel S , et al. (2010)
c.5191G>T p.Ala1731Ser missense_variant Familial (n=2), unknown (n=2) Maternal (n=2) - 25560758 Peykov S , et al. (2015)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2062-22283G>A;c.298-22283G>A - intron_variant - - - 29934968 Bai Y , et al. (2018)
SFARI Gene score
1

High Confidence

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619). Integrated Transmission and De Novo Association (TADA) analysis of small de novo deletions and exome mutations from the Simons Simplex Collection, the Autism Sequencing Consortium, and the Autism Genome Project identified SHANK2 as a ASD risk gene with a false discovery rate (FDR) 0.01 (Sanders et al., 2015). Analysis of cortical neurons from induced pluripotent stem cells derived from two ASD probands with de novo mutations in SHANK2 that were originally reported in Berkel et al., 2010 demonstrated increases in dendritic length and complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents compared to controls (Zaslavsky et al., 2019).

Score Delta: Decreased from 2 to 1

1

High Confidence

See all Category 1 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.

10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619). Integrated Transmission and De Novo Association (TADA) analysis of small de novo deletions and exome mutations from the Simons Simplex Collection, the Autism Sequencing Consortium, and the Autism Genome Project identified SHANK2 as a ASD risk gene with a false discovery rate (FDR) 0.01 (Sanders et al., 2015). Analysis of cortical neurons from induced pluripotent stem cells derived from two ASD probands with de novo mutations in SHANK2 that were originally reported in Berkel et al., 2010 demonstrated increases in dendritic length and complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents compared to controls (Zaslavsky et al., 2019).

Reports Added
[New Scoring Scheme]
7/1/2019
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619). Integrated Transmission and De Novo Association (TADA) analysis of small de novo deletions and exome mutations from the Simons Simplex Collection, the Autism Sequencing Consortium, and the Autism Genome Project identified SHANK2 as a ASD risk gene with a false discovery rate (FDR) 0.01 (Sanders et al., 2015). Analysis of cortical neurons from induced pluripotent stem cells derived from two ASD probands with de novo mutations in SHANK2 that were originally reported in Berkel et al., 2010 demonstrated increases in dendritic length and complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents compared to controls (Zaslavsky et al., 2019).

4/1/2019
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

1/1/2019
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

10/1/2018
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

7/1/2018
2.1
icon
2

Decreased from 2.1 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

4/1/2017
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

Reports Added
[Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.2011] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.2012] [Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangemen...2013] [Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.2013] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Identification and functional characterization of rare SHANK2 variants in schizophrenia.2015] [The Shank family of scaffold proteins.2000] [The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal.2005] [AnkyrinG is required to maintain axo-dendritic polarity in vivo.2009] [BetaPix up-regulates Na? exchanger 3 through a Shank2-mediated protein-protein interaction.2010] [Activity induced changes in the distribution of Shanks at hippocampal synapses.2010] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness.2016] [Genome-wide characteristics of de novo mutations in autism.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
7/1/2016
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

4/1/2016
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

Reports Added
[Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.2011] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.2012] [Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangemen...2013] [Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.2013] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Identification and functional characterization of rare SHANK2 variants in schizophrenia.2015] [The Shank family of scaffold proteins.2000] [The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal.2005] [AnkyrinG is required to maintain axo-dendritic polarity in vivo.2009] [BetaPix up-regulates Na? exchanger 3 through a Shank2-mediated protein-protein interaction.2010] [Activity induced changes in the distribution of Shanks at hippocampal synapses.2010] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness.2016]
1/1/2016
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

Reports Added
[Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.2011] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.2012] [Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangemen...2013] [Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.2013] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Identification and functional characterization of rare SHANK2 variants in schizophrenia.2015] [The Shank family of scaffold proteins.2000] [The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal.2005] [AnkyrinG is required to maintain axo-dendritic polarity in vivo.2009] [BetaPix up-regulates Na? exchanger 3 through a Shank2-mediated protein-protein interaction.2010] [Activity induced changes in the distribution of Shanks at hippocampal synapses.2010] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
1/1/2015
2
icon
2

Decreased from 2 to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 (one nonsense, one frameshift insertion) have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619).

Reports Added
[The Shank family of scaffold proteins.2000] [The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal.2005] [AnkyrinG is required to maintain axo-dendritic polarity in vivo.2009] [BetaPix up-regulates Na? exchanger 3 through a Shank2-mediated protein-protein interaction.2010] [Activity induced changes in the distribution of Shanks at hippocampal synapses.2010] [Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.2011] [Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.2012] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangemen...2013] [Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.2013] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014]
4/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare CNVs in the SHANK2 gene have been observed with autism (Berkel et al., 2010; Pinto et al., 2010).

Krishnan Probability Score

Score 0.76536060432427

Ranking 22/25841 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.
ExAC Score

Score 0.99992016961575

Ranking 649/18225 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
Iossifov Probability Score

Score 0.981

Ranking 43/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.00010216837336994

Ranking 13/18665 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).
Larsen Cumulative Evidence Score

Score 101

Ranking 8/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.34092011060786

Ranking 2127/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CFTR cystic fibrosis transmembrane conductance regulator homolog Mouse Protein Binding 12638 P26361
SLC9A3 solute carrier family 9 (sodium/hydrogen exchanger), member 3 Rat Protein Binding 24784 P26433
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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