Submission Details

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; these variants and this phenotype are not included as part of 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 has been added, and the classification remains the same.

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.