SHANK2
protein-codingSH3 and multiple ankyrin repeat domains 2, the group of PDZ domain containing|Sterile alpha motif domain containing|Ankyrin repeat domain containing|MicroRNA protein coding host genes
Gene summary
This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density of excitatory synapses. Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, and an SH3 domain. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the postsynaptic densities of the adult and developing brain. Alterations in the encoded protein may be associated with susceptibility to autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
- CORTBP1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~784.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*SHANK2* variants have been reported in the literature in association with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia. Currently, only missense changes have been reported in individuals with schizophrenia; this phenotype was not included in this curation. Due to observations of loss of function (LoF) variants in both ASD and ID, this gene has been curated using the disease term complex neurodevelopmental disorder. *SHANK2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder (specifically, ASD and ID) in 2010 (Berkel et al., PMID: 20473310). Eight LoF variants (exonic deletions, nonsense, and frameshift) that have been reported in nine probands in seven publications (PMIDs: 20473310, 20531469, 22495306, 26350204, 28554332, 30564305, 30763456) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. All the scored variants were part of large cohort studies that did not necessarily include detailed descriptions of each individual’s phenotype. *SHANK2* is significantly constrained for LoF variants (pLI = 1, LOEUF = 0.42, gnomAD v4.1.0). The mechanism of pathogenicity is haploinsufficiency, based on protein truncating variants in affected individuals and functional studies in cells derived from an affected individual (PMID: 30911184). Missense variants have been observed in individuals with ASD and/or ID (PMID: 22346768); however, most of these variants were inherited from reportedly unaffected parents. These missense changes are currently classified as variants of uncertain significance and were not scored as part of this curation; additional evidence is needed to understand their role in disease causality. This gene-disease relationship is also supported by experimental evidence, including biochemical function (PMID: 28179641), patient-derived induced pluripotent stem cells (PMID: 30911184), and mouse models (PMID: 30072871). *SHANK2* is a member of the SHANK gene family (*SHANK1*, *SHANK2*, and *SHANK3*), which encodes scaffolding proteins that are enriched in the postsynaptic density of glutamatergic synapses and play a crucial role in synaptic development and function. *SHANK3* and *SHANK1* are also involved in neurodevelopmental disorders with ASD and ID. In summary, there is definitive evidence supporting the relationship between *SHANK2* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 17, 2019 (SOP Version 6). As of October 2025, this record underwent administrative updates to include edits to the evidence summary and update scoring to be consistent with SOP Version 11. No new evidence was added, and the classification remains the same.
Inheritance Pattern: AD
Disease ID:MONDO:0013265
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013265
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013265
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SHANK2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012309.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 14 | 124 | 4 | 142 | ||
| missense | 1 | 1 | 189 | 65 | 6 | 262 |
| nonsense | 7 | 13 | 5 | 25 | ||
| start loss | 1 | 1 | ||||
| frameshift | 15 | 19 | 16 | 50 | ||
| splice donor/acceptor (+/-2bp) | 4 | 8 | 12 | |||
| Total | 23 | 37 | 233 | 189 | 10 | 492 |
Highest pathogenic variant AF is 0.000022866976
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036441.2 | 24 | MANE Select | |
| Ensembl | ENSP00000469689.2 | 24 | MANE Select | |
| RefSeq | NP_001366155.1 | 16 | Standard | |
| RefSeq | NP_001427953.1 | 22 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glutamatergic synapse - Homo sapiens (human)
- Neuronal System
- Neurexins and neuroligins
- Protein-protein interactions at synapses
Biological Process
- synapse assembly
- learning
- adult behavior
- social behavior
- brain morphogenesis
Molecular Function
- protein binding
- SH3 domain binding
- receptor signaling complex scaffold activity
- GKAP/Homer scaffold activity
- ionotropic glutamate receptor binding
Cellular Component
- photoreceptor outer segment
- photoreceptor inner segment
- cellular_component
- cytosol
- neurofilament
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000338508
- Coding exons
- 33
- Length
- 649663
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125733
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.32 | 923 | 1.14e+3 | 0.807 | 0.0000800 | 12010 |
| Missense (PolyPhen) | 186 | 266.31 | 0.69843 | 2734 | ||
| Synonymous | -0.224 | 523 | 517 | 1.01 | 0.0000427 | 3812 |
| Loss of Function | 5.51 | 26 | 78.8 | 0.330 | 0.00000459 | 884 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors, and the actin-based cytoskeleton. May play a role in the structural and functional organization of the dendritic spine and synaptic junction.;
- Disease
- DISEASE: Autism 17 (AUTS17) [MIM:613436]: A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate mental retardation. {ECO:0000269|PubMed:20473310}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Essentials
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.788
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |