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SPACNACS is a crowdsourcing initiative to provide information about Copy Number Variations of the Spanish population to the scientific/medical community. We accept submissions from WES or WGS, no matter whether these come from healthy or diseased individuals.

The sequences were contributed by different consortiums and projects, including groups from the Spanish Network for Research in Rare Diseases, CIBERER, results from the EnoD, the Project Genome 1000 Navarra and other research groups and initiatives across Spain.

SPACNACS is an open resource available at http://csvs.clinbioinfosspa.es/spacnacs

Table of content

1. Web interface
   1. Overview
   2. Search panel
   3. Filtering status panel
2. CNV annotations
3. Beacon
4. Citation

Web interface

The web interface has 3 main sections:

• Browser panel (Fig 1.A). Consists on an embedded Integrative Genomics Viewer preloaded with the Spanish CNV database and other useful tracks.
• Search and selection panel (Fig 1.B). We provide several filters for specifying the genomic region and the data to be shown.
• Filtering status panel (Fig 1.C). Shows information about the active filters. By default, the whole dataset is shown.

Browser panel

IGV provides several navigation controls for specifying the genomic region to view. A ruler indicating the extent of the current region is displayed below the toolbar, and the size of the region and its genomic coordinates are displayed in the toolbar.

• Select a chromosome. The chromosome dropdown menu in the toolbar includes an entry for every chromosome or contig in the reference genome. Selecting a chromosome from the menu will set the view to include the whole chromosome. The ruler also includes a cytoband ideogram.

• Enter genomic coordinates. In the text box where the genomic coordinates are displayed, you can type the coordinates of the region you want to view (e.g. chr17:41,195,312-41,278,500). The thousands separator is optional, but the chromosome name is required.

• Spanish CNVs database. The CNVs track displays Copy Number Variations in the spanish population that fulfill the current filtering criteria. We provide and extensive annotation of CNVs with clinical relevant databases (see CNV annotations). Use the Search panel to filter out CNVs according to the CNV type and annotations.

• World populations CNVs. CNVs derived from gnomad and 1000 genomes projects are provided as two additional tracks. We keep duplications, deletions and Multiallelic CNVs (MCNVs). Frequencies for MCNV are sumarized in deletions (CN0 and CN1) and duplications (CN3 or more). Click on an element to display detailed information.

• Regularoty regions. Displays the current set of regulatory features as provided by ensembl. See regulatory features for additional information.

• Clinvar structural variants. This track contains known clinical relevant Copy number gain, copy number loss, duplication and deletion from clinvar.

Search panel

This section controls the CNVs displayed in the CNVs track. By default, the whole dataset is displayed.

• Genomic view. Navigation along the genome can be done by specifying a locus (either in hg19 or GRCh37 nomenclature) or by looking for a specific gene. Canonical gene names as well as synonyms are supported. Use the gene text box to find the desired gene and click the plus sign to apply the filter.

• Variant type. Use this filter to show deletions, duplications or both types of CNVs.

• Annotation. We provide and extensive annotation of CNVs with clinical relevant databases (see CNV annotations). Select the annotations you are interested in, type some words to see suggestions and use the plus button to apply the filter. For example, filtering by intellectual disability (C3714756) in DisGeNET will show only CNVs overlapping genes associated with this disease in DisGeNET. Multiple filters are allowed.

• Frequency. CNVs frecuency for each CNV is calculated as the ratio of individuals having at least one CNV overlapping it. For non coding regions, only WGS are taken into account. Please, bear in mind that the frecuency may vary depending on the method used to calculate it.

• Samples. Despite gene pleiotropy cannot be completely ruled out, samples were binned at higher disease ICD10 categories. The main objetive is using the repository as a pseudo-control population for finding new disease-causing CNVs, with the idea that ‘disease A is a healthy control for disease B’. Additionally, samples can also be filtered out according to their main HPO or the gender.

• Sequencing type.Use this filter to show exomes, genomes or both. By default is checked genome.

• Pipeline. This filter is used to select the set of bioinformatics algorithms used. Currently there is information obtained through manta and gridss.

Filtering status panel

The filtering status section provides a summary of the filters applied to the CNV database. Default filters includes the whole database. Use the "X" button to remove a filter or the Search panel to add or remove filters.

In addition, in this sections there is a "Go to" button . Steps example:

1. You search in the Search panel for a locus (region or gene).
2. You navigate in igv (you can zoom with - or + button, selected another chromosme from selection, or move on this chromosome...).

3. Click the button "Go to".
4. If you want remove this anchor, remove the region or gene filter by clicking "X" button.

IGV Buttons

• Cursor guide: show line cursor.
• Center line: show line in the center from IGV.
• Track: Show/Hide name tracks.
• Sample name: Show/Hide name from files.
• Save SGV: Download image.
• "+" or "-" : Increases or decreases the locus.
• button:
  • Set track height: Increases or decreases the height of the track that displays the information.
  • Display mode: Depending on the type of track display the information in different ways (squish, spand or collapse).

NOTE: In the case of the CNV track, use scroll to display information for all samples.

CNV annotations

We provide and extensive annotation of CNVs with clinical relevant databases. A CNV is annotated with some specific genomic region feature if it is overlapped.

• Clinvar database. ClinVar is a freely accessible, public archive of reports of the relationships among human variations and phenotypes, with supporting evidence. It also provides gene-disease relationships.

• DisGeNET. DisGeNET is a discovery platform containing a collections of genes and variants associated to human diseases. DisGeNET integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature.

• Gene Ontology Annotation (GOA). The GOA program aims to provide high-quality Gene Ontology (GO) annotations to proteins in the UniProt Knowledgebase (UniProtKB), RNA molecules from RNACentral and protein complexes from the Complex Portal. GOA files contain a mixture of manual annotation and computationally assigned GO terms describing gene products.

• Clingen. ClinGen is a National Institutes of Health (NIH)-funded resource dedicated to building a central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. It provides a curated gene dosage sensitivity database.

• The Human Phenotype Ontology. The Human Phenotype Ontology HPO provides a standardized vocabulary of phenotypic abnormalities encountered in human disease. We provide HPO annotations derived directly from gene-phenotipe links and from the patient network analysis carried out by E. Rojano et at.

• UCSC. The wgEncodeEH000322 track from UCSC provides information about the mappability of the genome. This annotation can be useful to detect false positives and biases in CNV prediction technologies/tools.

Beacon

SPACNACS implements a Beacon (version 1.0), a standard protocol used to query the database to check whether a specific region is involved in a CNV.

The Beacon is an initiative of the Global Alliance for Genomics & Health (GA4GH) that allows genomic data sharing across federated networks.

The Beacon is a web-accessible service that can be queried for information about one specific allele at a time. Here,
the Beacon allows queries on amplifications or deletions that involve regions.

Since the definition of the boundaries of the CNVs is often difficult, the Beacon allows querying with ranges.

For example, CNV: 1:8:22,138,284-22,138,339

Steps:

1. Search within an interval of +/- 10 nucleotides the query would be as follows (Beacon is based-0):

• chromosome: 8
• start: 22138273-22138293 (startMin-startMax)
• end: 22138328-22138348 (endMin-endMax)

2. Use this url

   https://juliet.clinbioinfosspa.es:8443/spacnacs-ga4gh-beacon-v1/query?referenceName=[chromosome]&referenceBases=N&assemblyId=GRCh37&startMin=[starMin]&startMax=[starMax]&endMin=[endMin]&endMax=[endMax]

Generate url with CNV data:

• https://juliet.clinbioinfosspa.es:8443/spacnacs-ga4gh-beacon-v1/query?referenceName=8&referenceBases=N&assemblyId=GRCh37&startMin=22138273&startMax=22138293&endMin=22138328&endMax=22138348

3. Result:

   

SPACNACS is participating in the definition of Beacon specifications for CNV-related queries in the new Beacon 2.0 standard, currently under development .

Citation

By downloading data from the Spanish CNV DataBase you accept the obligation of acknowledge its use in any publication, presentation, conference, poster or any public event in which you present results obtained in any way using the data downloaded.

To acknowledge the use of Spanish CNV Database data use a sentence similar to this one: “These results were obtained using Spanish CNV DataBase data (https://csvs.clinbioinfosspa.es/spacnacs/) and in any publication you must cite the reference:

"Daniel López-López, Gema Roldán, Jose L Fernández-Rueda, Gerrit Bostelmann, Rosario Carmona, Virginia Aquino, Javier Perez-Florido, Francisco Ortuño, Guillermo Pita, Rocío Núñez-Torres,Anna González-Neira; CSVS Crowdsourcing Group; María Peña-Chilet, Joaquin Dopazo. doi:https://doi.org/10.1186/s40246-023-00466-8."