• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
SHANK2 (HGNC:14295) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
SH3 and multiple ankyrin repeat domains 2
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
CORTBP1
Alias symbols
CTTNBP1, ProSAP1, SHANK, SPANK-3
%HI
45.57(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0(Read more about gnomAD pLI score)
LOEUF
0.46(Read more about gnomAD LOEUF score)
Cytoband
11q13.3-q13.4
Genomic Coordinates
GRCh37/hg19: chr11:70313959-70963623 NCBI Ensembl UCSC
GRCh38/hg38: chr11:70467854-71253228 NCBI Ensembl UCSC
MANE Select Transcript
NM_012309.5 ENST00000601538.6 (Read more about MANE Select)
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. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-18172
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
10/26/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • complex neurodevelopmental disorder Monarch
HI Evidence:
  • PUBMED: 20473310
    Berkel et al 2010. performed genome-wide microarray analysis for CNVs in a German cohort of 184 unrelated individuals with intellectual disability along with a parallel study of 396 Canadian ASD cases. All ASD cases were diagnosed using the Autism Diagnostic Interview–revised and Autism Diagnostic Observation Schedule measures (supp data). Authors identified 2 de novo SHANK2 deletions, one of which spanned 120 kb in size involving loss of exon 7 (case M01812A011) and the other 69 kb in size involving loss of exons 6 and 7 (case SK0217-003). The patient with loss of exons 6 and 7 was reported to have ASD while the patient with the deletion involving loss of only exon 7 had mild to moderate intellectual disability (Table 1). Both deletions disrupt the highly conserved PDZ domain of SHANK2, causing a frameshift and presumably functional loss of one allele. SHANK2 CNVs (losses and gains) were absent in the Database of Genomic Variants and in 5,023 controls of European ancestry. The authors also sequenced the exons of the neuronal isoform of SHANK2 (SHANK2_1, see Fig 1a in paper) in the same cohort of 184 individuals with intellectually disability and 396 individuals with ASD already tested by microarray. This was done in parallel with 659 controls of European ancestry for the same exons. Variants were identified among 8 different individuals comprising one de novo nonsense mutation R462X reported as having autism (case SK0441) and six missense variants inherited from an unaffected parent (R26W, P208S, S231Y, R1048W, T1127M and A1350T, see Supp Fig S3) and a microduplication of 6 nucleotides (L1008_P1009dup). With the exception of one variant (P208S) that was detected twice (in a case with intellectual disability and an ASD case), all other variants were found only once. None of these variants were identified in the 2 individuals carrying the de novo deletion, and none were detected in controls or in dbSNP (build 130). Parents transmitting the variants were undiagnosed for ASD but in some instances showed depression and/or anxiety (mothers of A1350T and the P208S variant). Siblings carrying the same missense variant as the ASD patient showed a similar phenotype or milder symptoms like speech delay, attention difficulties, articulation difficulties, or anxiety.
  • PUBMED: 22346768
    Leblond et al 2012 genotyped 260 patients with ASD using Illumina 1M Duo SNP arrays. A de novo 421.2 kb deletion (Patient AU038_3) affecting exons 5-16, which altered all SHANK2 isoforms, within SHANK2 in a male patient with autism, moderate ID, language delay, and minor signs of dysmorphism were observed. Of note, the same patient with the de novo 421.2 kb deletion carried a second hit involving a maternally inherited 496 kb duplication encompassing CHRNA7 in the BP5 region of chromosome 15q13. SHANK2 deletions were absent in more than 5000 controls and not listed in the DGV. Of note, as of May 2018, the ClinGen Dosage Sensitivity working group has curated duplications at 15q13.3 involving CHRNA7 as "dosage sensitivity unlikely" (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46295). Authors also identified an additional 496 kb duplication of CHRNA7 at 15q11q13 in patient AU038_3 and patient 5237_3 ( with a 66 kb de novo deletion reported by Pinto et al 2010). A second Pinto et. al. patient 6319_3 with a 68 kb de novo deletion of SHANK2 showed a 468 kb deletion involving CYFIPI at 15q11.2 between BP1-BP2, both regions proposed as susceptibility genes for neuropsychiatric disorders. Authors suggest that although the numbers are low the findings suggest possible epistasis of the NRXN-NLGN-SHANK pathway and 15q11-q13 CNVs between the two loci.
  • PUBMED: 20531469
    Pinto et al (2010), analyzed rare copy number variations <1% using dense genotyping arrays in 996 ASD individuals of European ancestry to 1,287 matched controls. Two de novo exonic deletions were identified in male probands, a 66 kb loss in ASD case 5237_3 and 68 kb loss in ASD case 6319_3. No CNVs were identified in four control datasets (SAGE controls and three independent control cohorts) containing 4,964 samples. Patient 5237_3 was diagnosed with autism associated with below average non-verbal IQ and language, minor dysmorphic features. Patient 6319_3 was diagnosed with pervasive developmental disorder-not otherwise specified and intellectual disability, and also had a paternally inherited 15q11.2 BP1-BP2 deletion (known neurodevelopmental disorder susceptibility locus).
  • PUBMED: 35456494
    Doddato et al. 2022 reported a patient with mild intellectual disability including language delay with a de novo stop-gain variant c.334C>T, p.(Gln112*) identified by exome sequencing. The variant is an early truncating variant that abolishes the major domains of the protein. The patient presented with speech delay and mild neuromotor delay but not autism spectrum disorder. In addition, the authors summarize previously reported cases of de novo LOF variants in SHANK2.
  • PUBMED: 32987185
    Caumes et al 2020 reported the molecular and clinical presentation of two patients carrying protein truncating variants of SHANK2. Pateint 1 was identified with a de novo frame-shift variant c.1322del p.(Ile441Thrfs*8). Patient 1 presented with a mild intellectual disability and autism spectrum disorder, sleep disorder. Patient 2 was identified with a de novo frame-shift variant c.132dup p.(Asp45Argfs*3). Patient 2 presented with autism, moderate intellectual disability, and anxiety.
  • PUBMED: 25188300
    Leblond et al, 2014 performed a meta-analysis of the SHANK gene family (SHANK1, SHANK2, SHANK3) copy number and coding sequencing variants in patients with ASD in order to determine the prevalence and clinical relevance. The meta-analysis utilized previously published data. SHANK2 deletions were identified in 0.05% (3 of 5657) patients with ASD and were not seen in 19,163 controls. The three deletions identified were de novo and disrupted coding sequences. The patients also displayed developmental delay, mild motor delay, significant language delay and minor dysmorphic features. No SHANK2 duplications were identified. These findings suggest enrichment of SHANK2 deletions in the clinical population, but the result was not statistically significant, likely due to the small number of observations. In addition one de novo truncating variant (p.R841Ter) was identified in the sequencing analysis arm of the study (0.12%, 1/851 ASD patients), and no truncating variants were seen among 1090 controls. The authors also observed rare coding-sequence variants predicted as damaging in 4.58% of the patients with ASD compared with 2.66% of the controls (Fisher's exact test two-sided, P = 0.025, OR = 1.76, 95% CI = 1.05–2.97). Two additional patients carrying de novo alterations of SHANK2 were identified through clinical screening, and were not part of the prevalence cohort described above. Patient AUL_001 had a t(1;7;11) de novo translocation with the breakpoint with intron 14 of the SHANK2 gene. Patient AUL_001 presented with autism, global developmental delay, severe intellectual disability/non-verbal, neonatal hypotonia and dysmorphic features. The second patient RDB_30769 was identified with a 1.8 Mb interstitial deletion that included multiple genes and whole gene deletion of SHANK2. Patient RDB_30769 presented with autism, global developmental delay, severe intellectual disability/non-verbal, dysmorphic features, slight hypotonia, and signs of cerebellar dysfunction.
HI Evidence Comments:
De novo loss-of-function (LOF) variants have been reported in a number of probands with a spectrum of neurodevelopmental features including autism spectrum disorders (ASD), intellectual disability, developmental delay, language delays, and mild dysmorphic features. This evidence supports haploinsufficiency of SHANK2 in association with complex neurodevelopmental disorders (NDD). Additional de novo LOF variants have been reported in studies of large NDD cohorts (Wang 2020 PMID 33004838; Satterstrom 2020 PMID 31981491; Zhou 2022 PMID 35982159). However, some of these studies reanalyzed previously reported cohorts, and specific clinical information was not always available, so we have included detailed reviews of these studies. Of note, computational haploinsufficiency predictors are not consistent with loss of function constraint (pLI=0). The presence of a number of nonsense, frameshift, and deletion variants in population databases such as gnomAD and DGV may call into question whether SHANK2 tolerates LOF variation. This seemingly contradictory evidence is explained by differences in transcript-level constraint. The longest SHANK2 transcript is used for pLI determination in gnomAD, but this transcript has little to no expression in the brain; when considering the shorter brain-specific transcript in gnomAD, the pLI=1, consistent with constraint against LOF variation in this particular transcript, as reviewed in PMID: 32599522. Please see figure 2 of PMID 32599522 and the gnomAD SHANK2 page (https://gnomad.broadinstitute.org/gene/SHANK2) for clear visualization of transcript-level constraint. Clinicians and investigators may wish to use caution in considering the effects of LOF variants located outside of the brain-specific transcript. While numerous missense variants have also been reported in associated with NDD, many of these were inherited from unaffected parents and/or are found in population databases. The clinical significance of missense variants in SHANK2 remains less clear, and this assessment of haploinsufficiency focused solely on nonsense, frameshift, and gross deletion variants predicted to result in LOF. Additional PMIDs: PMID 30763456 Zho et al. 2019, identified a de novo frameshift deletion c.2540_2541del p.Ser847* with autism, severe language disorder and social deficit, and sleep disorder. PMID 28554332 Bowling et al. 2017, identified a patient 00143-C with a de novo frameshift variant c.1896 dupA (p.ASP633Argfs) presenting with moderate intellectual disability, speech delay, ADHD and sensory issues. PMID 30564305, Guo et al. 2018, identified a patient HN0112.p1 with a de novo stop-gain c.87C>G p.(Tyr29*) in the SHANK2 gene with ASD, ID, speech delay, repetitive behavior and febrile seizures infancy.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
To date, no gross duplications/insertions reported in literature

Genomic View

Select assembly: (NC_000011.9) (NC_000011.10)