# Copy Number Variation: Methods and Clinical Applications
## 4 Clinical Interpretation of CNVs
To ensure this, existing standards for evaluating CNVs were recently updated, and detailed recommendations for the interpretation and reporting of constitutional CNVs were published [10]. These recommendations comprise a semiquantitative point-based scoring system in which evidence categories with assigned relative weight were determined. When evaluating individual CNVs, genomic content, dosage sensitivity, predicted functional effect, clinical overlap with patients in the literature, evidence from case and control databases (Table 3), and de novo occurrence or inheritance patterns are considered [10]. Using this scoring system, any evaluated CNV should be assigned to one of the five above mentioned main classes of clinical impact [95]. It was also demonstrated that topologically associated domains, in which structural alteration results in various malformations, may increase clinical suspicion of pathogenicity for variants of uncertain significance. This piece of information, among others, may help in the clinical interpreta  
\begin{table}
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**Tool** & **Description** & **Operating System** & **Availability** & **Reference** \\ \hline \multirow{8}{*}{cnvScan} & A CNV screening and annotation tool to improve the clinical utility of computational CNV prediction from exome sequencing data. The screening step evaluates CNV prediction using quality scores and refines it using an in-house CNV database. The annotation step uses multiple external databases from three groups: gene and functional efficient datasets, known CNVs from public databases and clinically significant datasets. & Linux & Free-software license & [101] \\ \hline \multirow{4}{*}{CNSpector} & A web-based tool for the visualization and clinical diagnosis of CNVs from NGS data. It represents a multi-scale interactive browser that shows CNVs in the context of other relevant genomic features to enable faster clinical reporting. & MS Windows Mac OS X Linux & Free-software license & [102] \\ \hline \multirow{4}{*}{CNView} & A tool for normalized visualization, statistical scoring and annotation of CNVs from population-scale WGS datasets having six sequential steps: (i) matrix filtering, (ii) matrix compression, (iii) intra-sample normalization, (iv) inter-sample normalization, (v) coverage visualization, and (vi) genome annotation. & MS Windows Mac OS X Linux & Free-software license & [103] \\ \hline \multirow{4}{*}{SVScore} & A VCF annotation tool that predicts the impact of SVs based on SNP pathogenicity scores across relevant genomic intervals for each SV. The tool assigns a very simple aggregate pathogenicity score to an SV based on overlapping SNP pathogenicity scores. Multiple options for aggregation are supported: maximum, sum, mean and mean of the top N scores. & Linux & Free-software license & [104] \\ \hline \multirow{4}{*}{SG-ADVISER-CNV} & A suite (consisting of an annotation pipeline and a Webserver) for CNV detection and interpretation by performing in-depth annotations and functional predictions for CNVs. The tool is designed to allow users with no prior bioinformatics expertise to handle large volumes of CNV data. & MS Windows Mac OS X Linux & \multirow{4}{*}{NA} & \multirow{4}{*}{[105]} \\ \cline{1-1} \cline{2-4}  & A browser-based tool for quick evaluation of the clinical relevance of a CNV in the context of TADs. It allows to input a chromosome number, genomic coordinates, and phenotypic information and relate this data to nearby TAD boundaries and genes. & MS Windows Mac OS X Linux & \multirow{4}{*}{Freely available Linux} & \multirow{4}{*}{[106]} \\ \hline \multirow{4}{*}{CNSVScope} & A tool for CNV relationship data analysis and visualization, allowing users to create interaction maps, discover CNV map domains, annotate gene interactions, and create interactive visualizations of these CNV interaction maps.