CHANGELOG¶

0.6.2 - June 30th 2021¶

Data updates: ClinVar, PanelApp, GWAS catalog, CIViC, CancerMine, dbNSFP, KEGG, Disease Ontology/EFO, Open Targets Platform, UniProt KB, GENCODE
Software upgrades: R v4.1, Bioconductor v3.13, VEP (104) ++
Improved GWAS track for cancer phenotypes

TOML-based configuration for CPSR is abandoned, all options to CPSR are now configured through the command-line parameters

Command-line options
- Previously set in TOML file
  - --pop_gnomad
  - --report_theme
  - --preserved_info_tags (previously custom_tags (TOML))
  - --custom_list_name
  - --gwas_p_value
  - --vcfanno_n_proc (previously n_vcfanno_proc (TOML))
  - --vep_n_forks (previously n_vep_forks (TOML))
  - --vep_pick_order
  - --vep_no_intergenic (previously vep_skip_intergenic (TOML))
- New options
  - --report_nonfloating_toc (NEW) - add the TOC at the top of the HTML report, not floating at the left of the document
  - --report_table_display (NEW) - choose level of comprehensiveness in interactive data tables (full versus light (default))
Improved support for noncoding variant interpretation, primarily in the context of variants of uncertain significance (VUS). Annotations will show variants that disrupt/create microRNA target sites (dbMTS), and variants that overlap transcription factor binding sites (critical and non-critical positions). Genomic conservation scores (GERP) are also provided.
Approx. 100 protein-coding genes have been appended to the CPSR superpanel (panel 0)

Increased number of genes in panel 0: All genes in 42 virtual panels related to cancer conditions in Genomics England PanelApp now also contributes toward panel 0
Added option in main script (--clinvar_ignore_noncancer) that will exclude any query variants (from HTML report and TSV/JSON output) that have been reported and classified for non-cancer related conditions only (in ClinVar)
- this to exclude variants associated with non-cancer related phenotypes
For the variant biomarker table, the resolution of the reported biomarker mapping is highlighted with designated background colors for the gene (exact/codon - black vs. exon/gene - orange)

Bug in GWAS hits retrieval, Issue #30
Custom VCF tags (as specified by user in configuration file) not shown in output TSV files

Removed DisGeNET annotations from output (associations from Open Targets Platform serve same purpose)
Renamed report section Genomic Biomarkers to Variant Biomarkers
Option --incidental_findings changed back to --secondary_findings - recommended term to use according to ACMG
Removed MOD (mechanism-of-disease) from TSV output file

Data updates: ClinVar, GWAS catalog, GENCODE, CIViC, CancerMine, UniProt KB, dbNSFP, Pfam, KEGG, Open Targets Platform, Genomics England PanelApp
Software updates: VEP 101

All arguments to cpsr.py are now non-positional
Arguments to cpsr.py are divided into two groups: required and optional
secondary_findings is now coined incidental_findings
Option gwas:gwas_hits in CPSR configuration file is now optional argument --gwas_findings in cpsr.py
Option classification:clinvar_cpsr in CPSR configuration file is now optional argument --classify_all in cpsr.py
Option maf_imits:maf_gnomad in CPSR configuration file is now optional argument --maf_upper_threshold in cpsr.py
Option secondary_findings:show_sf in CPSR configuration file is now optional argument --incidental_findings in cpsr.py
Virtual panels is now displayed through HTML (previously static ggplot plot)
Settings section of report is now divived into three:
- Sample metadata
- Report configuration
- Virtual panel
Classifications of genes as tumor suppressors/oncogenes are now based on a combination of CancerMine citation count and presence in Network of Cancer Genes

Missing ACMG criterion for classification of silent and intronic variants outside of splice regions (ACMG_BP7)
Missing ACMG criterion for classification of variants in promoter and untranslated regions (ACMG_BP3)
Possibility to create custom virtual panel - any combination of genes from panel 0 provided as a single-column text file with argument --custom_list
Ensured that non-empty datatables pr. tier (ClinVar and Non-ClinVar) are set as the active tab
Improved documentation of variant classification in the References section
DOIs available for all references

Definition of pathogenic range (wrt to variant frequency) takes into account population- and position-specific allele numbers - no longer defined only by allele counts (i.e. AC) but by AC and AN
Moved virtual panel identifier from positional argument to optional argument (--panel_id) in cpsr.py

Ability to analyze custom panels, provided through option --custom_panel. Needs to be defined as BED file with four columns, i.e. chromosome, start, stop, genesymbol

Bug in cpsr_validate_input.py, GitHub Issue
Bug when there are zero variants with a ‘PASS’ status in VCF - omitting report generation

Bug in implementation of ACMG criteria; genes without a known loss-of-function mechanism were handled inappropriately
Bug in assignment of heterozygous/homozygous states (input VCF)
Bug in implementation of ACMG_PS1 - Same amino acid change as previously pathogenic variant
Improved consequence prioritisation for variants with transcript consequences in multiple, distinct cancer predisposition genes
Upper MAF threshold (as given by user) only applied for unclassified (i.e. non-ClinVar variants)
Handling of non-coding variants (synonymous, upstream_variants) in the report, no longer excluded

Section on genomic biomarkers; indicating which variants in the query VCF that overlaps with existing germline biomarkers (CIViC)