Human Gene Module / Chromosome 11 / SHANK2

SHANK2SH3 and multiple ankyrin repeat domains 2

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
12 / 23
Rare Variants / Common Variants
72 / 0
Aliases
SHANK2, CORTBP1,  CTTNBP1,  ProSAP1,  SPANK-3,  SHANK2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
11q13.3-q13.4
Associated Disorders
ASD, EPS, ID, EP
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 (23 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited The Shank family of scaffold proteins. Sheng M and Kim E (2000) No -
2 Highly Cited The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal. Hwang JI , et al. (2005) No -
3 Recent Recommendation AnkyrinG is required to maintain axo-dendritic polarity in vivo. Sobotzik JM , et al. (2009) No -
4 Recent Recommendation BetaPix up-regulates Na+/H+ exchanger 3 through a Shank2-mediated protein-protein interaction. Lee JS , et al. (2010) No -
5 Recent Recommendation Activity induced changes in the distribution of Shanks at hippocampal synapses. Tao-Cheng JH , et al. (2010) No -
6 Primary Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Berkel S , et al. (2010) Yes MR
7 Support Functional impact of global rare copy number variation in autism spectrum disorders. Pinto D , et al. (2010) Yes -
8 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
9 Support Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. Leblond CS , et al. (2012) Yes ID
10 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
11 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
12 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
13 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 -
14 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 -
15 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 -
16 Recent recommendation Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. Leblond CS , et al. (2014) Yes -
17 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Li J , et al. (2015) Yes -
18 Recent Recommendation Identification and functional characterization of rare SHANK2 variants in schizophrenia. Peykov S , et al. (2015) No -
19 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
20 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 -
21 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
22 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
23 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
Rare Variants   (72)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 20473310 Berkel S , et al. (2010)
c.1384C>T p.Arg462Ter stop_gained De novo - Simplex 20473310 Berkel S , et al. (2010)
c.76C>T p.Arg26Trp missense_variant Familial Paternal - 20473310 Berkel S , et al. (2010)
c.622C>T p.Pro208Ser missense_variant Familial Maternal Multiplex 20473310 Berkel S , et al. (2010)
c.3024_3029dup p.Leu1008_Pro1009dup2 inframe_insertion Familial Maternal - 20473310 Berkel S , et al. (2010)
c.3380C>T p.Thr1127Met missense_variant Familial Maternal - 20473310 Berkel S , et al. (2010)
c.4048G>A p.Ala1350Thr missense_variant Familial Maternal Multiplex 20473310 Berkel S , et al. (2010)
c.467A>G p.Lys156Arg missense_variant - - - 20473310 Berkel S , et al. (2010)
c.492C>T p.(=) synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.526+61G>A N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.527-18C>A N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.527-8G>T N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.569G>A p.Arg190His missense_variant - - - 20473310 Berkel S , et al. (2010)
c.640+11C>T N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.800-33C>T N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.924+19G>A N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.924+133G>C N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1061-81C>T N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1141+49G>A N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1148-109C>T N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1201A>C p.Lys401Gln missense_variant - - - 20473310 Berkel S , et al. (2010)
c.1284G>A p.(=) synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.302+14C>A N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1302+35G>A N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1303-54C>T N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
c.1316G>A p.Arg439His missense_variant - - - 20473310 Berkel S , et al. (2010)
c.1392G>T p.(=) synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.1763A>G p.Tyr588Cys missense_variant - - - 20473310 Berkel S , et al. (2010)
c.1923G>A p.(=) synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.2052G>A p.(=) synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.2823C>T p.(=) synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.3135C>T p.(=) synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.3324C>T p.(=) synonymous_variant - - - 20473310 Berkel S , et al. (2010)
c.3620C>T p.Pro1207Leu missense_variant - - - 20473310 Berkel S , et al. (2010)
c.3843-12T>C N/A intron_variant - - - 20473310 Berkel S , et al. (2010)
- - copy_number_loss De novo - - 20531469 Pinto D , et al. (2010)
- - copy_number_loss De novo - - 20531469 Pinto D , et al. (2010)
- - copy_number_loss De novo - - 22346768 Leblond CS , et al. (2012)
c.1327C>T p.Arg443Cys missense_variant - - - 22346768 Leblond CS , et al. (2012)
C>A p.Arg598Leu missense_variant - - - 22346768 Leblond CS , et al. (2012)
c.2149G>T p.Val717Phe missense_variant Familial Paternal Simplex 22346768 Leblond CS , et al. (2012)
C>T p.Ala729Thr missense_variant Familial Maternal Multiplex 22346768 Leblond CS , et al. (2012)
c.3484G>A p.Glu1162Lys missense_variant - - - 22346768 Leblond CS , et al. (2012)
C>T p.Gly1170Arg missense_variant Familial Maternal Simplex 22346768 Leblond CS , et al. (2012)
c.4126G>A p.Val1376Ile missense_variant - - - 22346768 Leblond CS , et al. (2012)
c.4605A>T p.Asp1535Asn missense_variant Familial Maternal Simplex 22346768 Leblond CS , et al. (2012)
A>G p.Leu1722Pro missense_variant Familial Paternal Simplex 22346768 Leblond CS , et al. (2012)
G>A p.Thr410Met missense_variant - - - 22346768 Leblond CS , et al. (2012)
C>T p.Ser557Asn missense_variant - - - 22346768 Leblond CS , et al. (2012)
C>T p.Met1717Ile missense_variant - - - 22346768 Leblond CS , et al. (2012)
c.2542insCA - frameshift_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.132G>A p.(=) synonymous_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - inversion De novo - Simplex 23315544 Schluth-Bolard C , et al. (2013)
- - translocation De novo - - 23350639 Chilian B , et al. (2013)
- - copy_number_loss De novo - Simplex 25188300 Leblond CS , et al. (2014)
- - translocation De novo - - 25188300 Leblond CS , et al. (2014)
- - nonsynonymous_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.1313C>T p.Thr438Met missense_variant Familial Maternal - 25560758 Peykov S , et al. (2015)
C>A p.Gly488Val missense_variant Unknown - - 25560758 Peykov S , et al. (2015)
c.1829C>A p.Ser610Tyr missense_variant Unknown - - 25560758 Peykov S , et al. (2015)
c.2069A>G p.Asn690Ser 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.3431C>T p.Pro1144Leu missense_variant Familial Maternal - 25560758 Peykov S , et al. (2015)
c.4822G>A p.Val1608Ile 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)
c.5191G>T p.Ala1731Ser missense_variant Familial (n=2), unknown (n=2) Maternal (n=2) - 25560758 Peykov S , et al. (2015)
- p.Ala578Val missense_variant Familial Maternal Multiplex 27001614 Homann OR , et al. (2016)
c.757C>T p.Arg253Ter stop_gained De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.3427G>A p.Ala1143Thr missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.1896dupA p.Asp633Argfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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).

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.

04-01-2017
2

Initial score established: 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] [Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangemen...2013] [Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness.2016] [Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.2012] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [AnkyrinG is required to maintain axo-dendritic polarity in vivo.2009] [Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.2011] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Genome-wide characteristics of de novo mutations in autism.2016] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Identification and functional characterization of rare SHANK2 variants in schizophrenia.2015] [BetaPix up-regulates Na+/H+ exchanger 3 through a Shank2-mediated protein-protein interaction.2010] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.2010] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.2013] [Activity induced changes in the distribution of Shanks at hippocampal synapses.2010] [The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal.2005] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013]
CNVs associated with SHANK2(1 CNVs)
11q13.3-q13.4 4 Duplication 7  /  4
Animal Models associated with SHANK2(14 Models)
SHANK2_1_KO_HM Genetic
SHANK2_2_KO_HT Genetic
SHANK2_3_KO_HM Genetic
SHANK2_3_KO_HM_CDPPB_H RESCUE-Pharmaceutical
SHANK2_3_KO_HM_CDPPB_L RESCUE-Pharmaceutical
SHANK2_3_KO_HM_DCS RESCUE-Pharmaceutical
SHANK2_4_KO_HT Genetic
SHANK2_5_KO_HM Genetic
SHANK2_5_KO_HM_CQ RESCUE-Pharmaceutical
SHANK2_6_KO_HT Genetic
SHANK2_6_KO_HT_L838417 RESCUE-Pharmaceutical
SHANK2_7_KO_HT Genetic
SHANK2_7_KO_HT_L838417 RESCUE-Pharmaceutical
SHANK2_8_CKO_HM Genetic
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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