Human Gene Module / Chromosome 17 / VAMP2

VAMP2vesicle associated membrane protein 2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
1 / 4
Rare Variants / Common Variants
8 / 0
Aliases
VAMP2, SYB2,  VAMP-2
Associated Syndromes
-
Chromosome Band
17p13.1
Associated Disorders
ID, ASD, EPS
Relevance to Autism

Salpietro et al., 2019 reported five unrelated individuals with de novo heterozygous variants in the VAMP2 gene presenting with a neurodevelopmental disorder characterized by axial hypotonia, intellectual disability, autistic features (with a diagnosis of ASD in two individuals), Rett syndrome-like features, EEG abnormalities with or without seizures, and delayed or absent speech. A de novo missense variant in VAMP2 had previously been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Molecular Function

The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Synaptobrevins/VAMPs, syntaxins, and the 25-kD synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. This gene is thought to participate in neurotransmitter release at a step between docking and fusion. The protein forms a stable complex with syntaxin, synaptosomal-associated protein, 25 kD, and synaptotagmin. It also forms a distinct complex with synaptophysin.

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Reports related to VAMP2 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Primary Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment Salpietro V , et al. (2019) No ASD or autistic features, epilepsy/seizures
3 Support Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan Sunaga Y et al. (2020) No ID, epilepsy/seizures
4 Support - Sanchis-Juan A et al. (2023) No -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.199G>C p.Ala67Pro missense_variant De novo - - 32336483 Sunaga Y et al. (2020)
c.109G>T p.Ala37Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.223T>C p.Ser75Pro missense_variant De novo - Simplex 30929742 Salpietro V , et al. (2019)
c.230T>C p.Phe77Ser missense_variant De novo - Simplex 30929742 Salpietro V , et al. (2019)
c.233A>C p.Gln78Pro missense_variant De novo - Simplex 30929742 Salpietro V , et al. (2019)
c.203G>C p.Arg68Pro missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.134_136del p.Val45del inframe_deletion De novo - Simplex 30929742 Salpietro V , et al. (2019)
c.135_137del p.Asp46del inframe_deletion De novo - Simplex 30929742 Salpietro V , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Salpietro et al., 2019 reported five unrelated individuals with de novo heterozygous variants in the VAMP2 gene presenting with a neurodevelopmental disorder characterized by axial hypotonia, intellectual disability, autistic features (with a diagnosis of ASD in two individuals), Rett syndrome-like features, EEG abnormalities with or without seizures, and delayed or absent speech. A de novo missense variant in VAMP2 had previously been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

7/1/2020
S
icon
S

Score remained at S

Description

Salpietro et al., 2019 reported five unrelated individuals with de novo heterozygous variants in the VAMP2 gene presenting with a neurodevelopmental disorder characterized by axial hypotonia, intellectual disability, autistic features (with a diagnosis of ASD in two individuals), Rett syndrome-like features, EEG abnormalities with or without seizures, and delayed or absent speech. A de novo missense variant in VAMP2 had previously been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Reports Added
[Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Salpietro et al., 2019 reported five unrelated individuals with de novo heterozygous variants in the VAMP2 gene presenting with a neurodevelopmental disorder characterized by axial hypotonia, intellectual disability, autistic features (with a diagnosis of ASD in two individuals), Rett syndrome-like features, EEG abnormalities with or without seizures, and delayed or absent speech. A de novo missense variant in VAMP2 had previously been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.6361060229675

Ranking 57/25841 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 0.83711760073938

Ranking 3707/18225 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 0.89411315772166

Ranking 5843/18665 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 0.3908488011355

Ranking 1556/20870 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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