Human Gene Module / Chromosome 19 / SHANK1

SHANK1SH3 and multiple ankyrin repeat domains 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 16
Rare Variants / Common Variants
60 / 0
EAGLE Score
14.65
Strong Learn More
Aliases
SHANK1, SPANK-1,  SSTRIP,  synamon
Associated Syndromes
-
Chromosome Band
19q13.33
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SHANK1 (16 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 -
7 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) Yes -
8 Recent Recommendation Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5 Scheefhals N , et al. (2019) No -
9 Recent Recommendation - May HJ et al. (2021) No ASD, epilepsy/seizures
10 Support - Paprocka J et al. (2021) Yes -
11 Support - Li D et al. (2022) Yes -
12 Recent Recommendation - Qin Y et al. (2022) Yes -
13 Support - Zhou X et al. (2022) Yes -
14 Support - Spataro N et al. (2023) Yes -
15 Support - Sheth F et al. (2023) Yes DD, ID
16 Recent Recommendation - Yue Qin et al. (2023) Yes -
Rare Variants   (60)
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.1198C>T p.Arg400Ter stop_gained De novo - - 34113010 May HJ et al. (2021)
c.2458+1G>A - splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
c.3355G>T p.Glu1119Ter stop_gained De novo - - 34113010 May HJ et al. (2021)
c.2416C>G p.Pro806Ala missense_variant Unknown - - 34968013 Li D et al. (2022)
c.2137C>T p.Arg713Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.2080C>T p.Pro694Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5838A>C p.Lys1946Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.650del p.Leu217Ter frameshift_variant De novo - - 34113010 May HJ et al. (2021)
c.2621G>A p.Arg874His missense_variant De novo - Simplex 35388181 Qin Y et al. (2022)
c.587C>T p.Ala196Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5417C>T p.Pro1806Leu missense_variant De novo - Simplex 35388181 Qin Y et al. (2022)
c.6304G>A p.Asp2102Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - 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.3488dup p.Ser1164ValfsTer4 frameshift_variant De novo - - 34113010 May HJ et al. (2021)
c.1424C>T p.Ser475Leu missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3330G>A p.Leu1110%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5704G>A p.Gly1902Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.376G>C p.Gly126Arg missense_variant De novo - Simplex 34912368 Paprocka J et al. (2021)
c.3314del p.Gly1105AlafsTer238 frameshift_variant De novo - - 34113010 May HJ et al. (2021)
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.4496_4499del p.Gln1499ProfsTer5 frameshift_variant De novo - - 34113010 May HJ et al. (2021)
c.1835C>T p.Ala612Val missense_variant Familial Maternal Simplex 35388181 Qin Y et al. (2022)
c.2621G>A p.Arg874His missense_variant Familial Maternal Simplex 35388181 Qin Y et al. (2022)
c.179G>A p.Arg60His missense_variant Familial Maternal Simplex 22503632 Sato D , et al. (2012)
c.5417C>T p.Pro1806Leu missense_variant Familial Maternal Simplex 35388181 Qin Y et al. (2022)
c.5776G>A p.Asp1926Asn missense_variant Familial Paternal Simplex 35388181 Qin Y et al. (2022)
c.6076G>A p.Gly2026Arg missense_variant Familial Maternal Simplex 35388181 Qin Y et al. (2022)
c.6110G>A p.Gly2037Asp missense_variant Familial Maternal Simplex 35388181 Qin Y et al. (2022)
c.877G>A p.Asp293Asn missense_variant Familial Maternal Simplex 22503632 Sato D , et al. (2012)
c.1105C>G p.Arg369Gly missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
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.3814_3815insGACGGCGGG p.Leu1272delinsArgArgArgVal inframe_indel Unknown - Unknown 31130284 Monies D , et al. (2019)
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
2

Strong Candidate

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 equivalentSHANK1mutations 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).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
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 equivalentSHANK1mutations 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).

Reports Added
[Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5.2019] [New Scoring Scheme]
7/1/2019
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 equivalentSHANK1mutations 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).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
1/1/2019
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 equivalentSHANK1mutations 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).

Reports Added
[SHANK1 polymorphisms and SNP-SNP interactions among SHANK family: A possible cue for recognition to autism spectrum disorder in infant age.2019]
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).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
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).

Reports Added
[Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.2015] [Excess of rare, inherited truncating mutations in autism.2015]
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).

Reports Added
[SHANK1 Deletions in Males with Autism Spectrum Disorder.2012] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014]
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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
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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