Human Gene Module / Chromosome 2 / SPTBN1

SPTBN1spectrin beta, non-erythrocytic 1

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
9 / 14
Rare Variants / Common Variants
59 / 0
Aliases
SPTBN1, ELF,  HEL102,  SPTB2,  betaSpII
Associated Syndromes
Tourette syndrome
Chromosome Band
2p16.2
Associated Disorders
ADHD, ASD, EPS
Relevance to Autism

A de novo nonsense variant and two de novo missense variants in the SPTBN1 gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the Autism Sequencing Consortium (Satterstrom et al., 2010), while rare inherited missense variants in this gene were identified in two Chinese ASD probands in Li et al., 2017. Rosenfeld et al., 2021 reported seven unrelated individuals with heterozygous SPTBN1 variants, all of whom presented with developmental delay and/or intellectual disability; three of these individuals were diagnosed with autism spectrum disorder, while autistic features were observed in a fourth. Additional de novo loss-of-function and missense variants in the SPTBN1 gene were observed in ASD probands from the MSSNG cohort and the SPARK cohort in Zhou et al., 2022. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SPTBN1 as a gene reaching exome-wide significance (P < 2.5E-06); association of SPTBN1 with ASD risk in this analysis was found to be driven predominantly by rare inherited loss-of-function variants transmitted from unaffected parents to affected offspring.

Molecular Function

Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats which are involved in dimer formation.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SPTBN1 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support De Novo Coding Variants Are Strongly Associated with Tourette Disorder Willsey AJ , et al. (2017) No -
3 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Recent Recommendation - Rosenfeld JA et al. (2021) No ASD, ADHD, epilepsy/seizures
6 Recent Recommendation - Cousin MA et al. (2021) No ASD or autistic features, ADD/ADHD, epilepsy/seizu
7 Support - Tuncay IO et al. (2022) Yes DD
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Recent Recommendation - Zhou X et al. (2022) Yes -
10 Support - Cirnigliaro M et al. (2023) Yes -
11 Support - Ana Karen Sandoval-Talamantes et al. (2023) Yes DD
12 Support - Ruohao Wu et al. (2024) Yes -
13 Support - Axel Schmidt et al. (2024) No -
14 Support - Mia O'Connell et al. () No DD, ID
Rare Variants   (59)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3909C>G p.Tyr1303Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.6775G>T p.Glu2259Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.466C>T p.Arg156Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.532G>A p.Ala178Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2405C>T p.Thr802Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2711G>A p.Arg904Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.549C>A p.Cys183Ter stop_gained De novo - - 33847457 Rosenfeld JA et al. (2021)
c.4931A>C p.Tyr1644Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7027G>T p.Gly2343Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5233C>T p.Arg1745Ter stop_gained Unknown - - 39039281 Axel Schmidt et al. (2024)
c.3198G>A p.Gln1066%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1471G>C p.Glu491Gln missense_variant Unknown - - 34211179 Cousin MA et al. (2021)
c.2549C>G p.Ala850Gly missense_variant Unknown - - 34211179 Cousin MA et al. (2021)
c.247C>T p.Arg83Ter stop_gained De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.475-1G>A - splice_site_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.647+1G>T - splice_site_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.549C>A p.Cys183Ter stop_gained De novo - Simplex 34211179 Cousin MA et al. (2021)
c.5961+2T>C - splice_site_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.2674G>T p.Glu892Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2284G>A p.Asp762Asn missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5794C>T p.Arg1932Trp missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3716G>A p.Gly1239Glu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.176C>T p.Thr59Ile missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.763+1G>A - splice_site_variant Familial Maternal - 33847457 Rosenfeld JA et al. (2021)
c.1210C>A p.His404Asn missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.613G>A p.Gly205Ser missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.614G>A p.Gly205Asp missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.740T>A p.Leu247His missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.749T>G p.Leu250Arg missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.765C>A p.Asp255Glu missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.802A>G p.Thr268Ala missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.803C>A p.Thr268Asn missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.803C>G p.Thr268Ser missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.811G>A p.Val271Met missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.824A>G p.His275Arg missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.427C>T p.His143Tyr missense_variant De novo - Simplex 35190550 Tuncay IO et al. (2022)
c.1032C>G p.Phe344Leu missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.1231C>T p.Arg411Trp missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.1232G>A p.Arg411Gln missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.3007C>T p.Arg1003Trp missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.3256G>A p.Ala1086Thr missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.5020T>C p.Ser1674Pro missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.5656G>C p.Glu1886Gln missense_variant De novo - Simplex 34211179 Cousin MA et al. (2021)
c.647+1G>T - splice_site_variant Unknown Not maternal - 33847457 Rosenfeld JA et al. (2021)
c.567-2_584delins17 p.? splice_site_variant De novo - - 33847457 Rosenfeld JA et al. (2021)
c.4873C>T p.Gln1625Ter stop_gained De novo - Simplex 39162370 Mia O'Connell et al. ()
c.3330G>C p.Glu1110Asp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.613G>A p.Gly205Ser missense_variant De novo - Simplex 33847457 Rosenfeld JA et al. (2021)
c.1005C>T p.Val335%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.4192G>A p.Gly1398Ser missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.3966A>G p.Glu1322%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.4041G>A p.Thr1347%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.5641G>A p.Asp1881Asn missense_variant De novo - Simplex 33847457 Rosenfeld JA et al. (2021)
c.5361G>A p.Trp1787Ter stop_gained Unknown Not maternal Multiplex 34211179 Cousin MA et al. (2021)
c.3908dup p.Tyr1303Ter frameshift_variant Unknown Not maternal - 33847457 Rosenfeld JA et al. (2021)
c.3007C>T p.Arg1003Trp missense_variant Familial Maternal Multiplex 34211179 Cousin MA et al. (2021)
c.5014C>T p.Arg1672Trp missense_variant Unknown - - 38003033 Ana Karen Sandoval-Talamantes et al. (2023)
c.5242G>A p.Gly1748Arg missense_variant Unknown Not maternal Simplex 39162370 Mia O'Connell et al. ()
c.3768_3773del p.His1257_Arg1258del splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
2S

Increased from to 2S

Krishnan Probability Score

Score 0.47855426018257

Ranking 8272/25841 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 0.99999999994737

Ranking 63/18225 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
Iossifov Probability Score

Score 0.995

Ranking 17/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.78019393582455

Ranking 1904/18665 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
Zhang D Score

Score 0.079972785133394

Ranking 6552/20870 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
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