Human Gene Module / Chromosome 19 / SHANK1

SHANK1SH3 and multiple ankyrin repeat domains 1

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
35 / 0
Aliases
SHANK1, SPANK-1,  SSTRIP,  synamon
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
19q13.33
Associated Disorders
-
Relevance to Autism

Rare mutations in the SHANK1 gene have been identified in individuals with ASD (Sato et al., 2012).

Molecular 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 via complexes with GKAP/PSD-95 and Homer, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction.

Reports related to SHANK1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary SHANK1 Deletions in Males with Autism Spectrum Disorder. Sato D , et al. (2012) Yes -
2 Recent Recommendation Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. Leblond CS , et al. (2014) Yes -
3 Recent Recommendation Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Mao W , et al. (2015) No -
4 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
5 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
6 Negative Association SHANK1 polymorphisms and SNP-SNP interactions among SHANK family: A possible cue for recognition to autism spectrum disorder in infant age. Qiu S , et al. (2019) Yes -
Rare Variants   (35)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Multiplex 22503632 Sato D , et al. (2012)
c.2458+1G>A p.? splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
- - copy_number_loss Familial Maternal Multi-generational 22503632 Sato D , et al. (2012)
c.16G>A p.Ala6Thr missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.5704G>A p.Gly1902Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.4438G>A p.Ala1480Thr missense_variant Unknown - Multiplex 22503632 Sato D , et al. (2012)
c.1358C>T p.Ala453Val missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.1631G>A p.Arg544His missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.4391C>T p.Thr1464Met missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.4442C>T p.Ala1481Val missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.6076G>A p.Gly2026Arg missense_variant Unknown - Unknown 25188300 Leblond CS , et al. (2014)
c.179G>A p.Arg60His missense_variant Familial Maternal Simplex 22503632 Sato D , et al. (2012)
c.877G>A p.Asp293Asn missense_variant Familial Maternal Simplex 22503632 Sato D , et al. (2012)
c.4363G>A p.Val1455Met missense_variant Familial Maternal Simplex 22503632 Sato D , et al. (2012)
c.5171T>A p.Leu1724His missense_variant Familial Maternal Simplex 22503632 Sato D , et al. (2012)
c.5776G>A p.Asp1926Asn missense_variant Familial Maternal Simplex 22503632 Sato D , et al. (2012)
c.5941C>T p.Arg1981Cys missense_variant Familial Paternal Simplex 22503632 Sato D , et al. (2012)
c.877G>A p.Asp293Asn missense_variant Familial Paternal Multiplex 22503632 Sato D , et al. (2012)
c.1322C>A p.Thr441Asn missense_variant Familial Paternal Multiplex 22503632 Sato D , et al. (2012)
c.1585G>A p.Gly529Arg missense_variant Familial Paternal Multiplex 22503632 Sato D , et al. (2012)
c.3037C>T p.Pro1013Ser missense_variant Familial Maternal Multiplex 22503632 Sato D , et al. (2012)
c.4361G>A p.Gly1454Glu missense_variant Familial Paternal Multiplex 22503632 Sato D , et al. (2012)
c.4442C>T p.Ala1481Val missense_variant Familial Maternal Multiplex 22503632 Sato D , et al. (2012)
c.4543G>T p.Gly1515Trp missense_variant Familial Paternal Multiplex 22503632 Sato D , et al. (2012)
c.4799C>T p.Thr1600Ile missense_variant Familial Paternal Multiplex 22503632 Sato D , et al. (2012)
c.4855T>A p.Ser1619Thr missense_variant Familial Paternal Multiplex 22503632 Sato D , et al. (2012)
c.4858A>G p.Thr1620Ala missense_variant Familial Paternal Multiplex 22503632 Sato D , et al. (2012)
c.4810C>A p.Pro1604Thr missense_variant Unknown Not maternal Simplex 22503632 Sato D , et al. (2012)
c.5779G>A p.Asp1927Asn missense_variant Unknown Not maternal Simplex 22503632 Sato D , et al. (2012)
c.6134G>T p.Gly2045Val missense_variant Unknown Not maternal Simplex 22503632 Sato D , et al. (2012)
c.101G>A p.Gly34Asp missense_variant Familial Paternal Multi-generational 22503632 Sato D , et al. (2012)
c.2207G>A p.Arg736Gln missense_variant Familial Paternal Multi-generational 22503632 Sato D , et al. (2012)
c.5420C>T p.Pro1807Leu missense_variant Familial Paternal Multiplex and simplex 22503632 Sato D , et al. (2012)
c.3947G>A p.Gly1316Asp missense_variant Familial (1 case), Unknown (1 case) Paternal (1 case) Unknown 22503632 Sato D , et al. (2012)
c.5387G>A p.Gly1796Glu missense_variant Familial (5 cases), Unknown (2 cases) Maternal (4 cases) & paternal (1 case) Unknown 22503632 Sato D , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Decreased from 3 to

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2018
3
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Decreased from 3 to

Description

3

10/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two deletions affecting SHANK1 were identified in Sato et al., 2012: a hemizygous SHANK1 deletion that segregated in a four-generation family in which male carriers, but not female carriers, had ASD with higher functioning; and a de novo SHANK1 deletion detected in an unrelated male individual with ASD with higher functioning. No equivalent SHANK1 mutations were found in >15,000 controls (P = 0.009) in this report (PMID 22503632). Rare inherited coding-sequence variants that were predicted to be damaging were statistically enriched in ASD cases vs. controls (P=0.012); rare SHANK1 variants observed in ASD cases were absent in an additional cohort of 500 control chromosomes (PMID 25188300). Mice deficient in SHANK1 exhibit reduced levels of ultrasonic vocalizations and scent marking behavior, reduced motor activity, and changes in learning and memory (PMIDs 18272690, 21695253). A promoter variant in SHANK1 led to significantly impaired auditory working memory both in schizophrenia cases (P < .001) and in subjects at risk for psychosis (P=0.044) (PMID 21901269).

4/1/2015
3
icon
3

Decreased from 3 to 3

Description

Two deletions affecting SHANK1 were identified in Sato et al., 2012: a hemizygous SHANK1 deletion that segregated in a four-generation family in which male carriers, but not female carriers, had ASD with higher functioning; and a de novo SHANK1 deletion detected in an unrelated male individual with ASD with higher functioning. No equivalent SHANK1 mutations were found in >15,000 controls (P = 0.009) in this report (PMID 22503632). Rare inherited coding-sequence variants that were predicted to be damaging were statistically enriched in ASD cases vs. controls (P=0.012); rare SHANK1 variants observed in ASD cases were absent in an additional cohort of 500 control chromosomes (PMID 25188300). Mice deficient in SHANK1 exhibit reduced levels of ultrasonic vocalizations and scent marking behavior, reduced motor activity, and changes in learning and memory (PMIDs 18272690, 21695253). A promoter variant in SHANK1 led to significantly impaired auditory working memory both in schizophrenia cases (P < .001) and in subjects at risk for psychosis (P=0.044) (PMID 21901269).

7/1/2014
icon
3

Increased from to 3

Description

Two deletions affecting SHANK1 were identified in Sato et al., 2012: a hemizygous SHANK1 deletion that segregated in a four-generation family in which male carriers, but not female carriers, had ASD with higher functioning; and a de novo SHANK1 deletion detected in an unrelated male individual with ASD with higher functioning. No equivalent SHANK1 mutations were found in >15,000 controls (P = 0.009) in this report (PMID 22503632). Rare inherited coding-sequence variants that were predicted to be damaging were statistically enriched in ASD cases vs. controls (P=0.012); rare SHANK1 variants observed in ASD cases were absent in an additional cohort of 500 control chromosomes (PMID 25188300). Mice deficient in SHANK1 exhibit reduced levels of ultrasonic vocalizations and scent marking behavior, reduced motor activity, and changes in learning and memory (PMIDs 18272690, 21695253). A promoter variant in SHANK1 led to significantly impaired auditory working memory both in schizophrenia cases (P < .001) and in subjects at risk for psychosis (P=0.044) (PMID 21901269).

Krishnan Probability Score

Score 0.47226453530261

Ranking 8813/25841 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 0.99999976094714

Ranking 227/18225 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
Sanders TADA Score

Score 0.94798113231253

Ranking 17497/18665 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 94

Ranking 10/461 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 -0.14257885294652

Ranking 13900/20870 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.
CNVs associated with SHANK1(1 CNVs)
19q13.33 17 Deletion-Duplication 28  /  110
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
SSTR2 somatostatin receptor 2 Rat Protein Binding 54305 P30680
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