Package: picus
# Picus
Pointed Interpretation of Clinical Variant Significance## Quick Install
* Linux&Mac> sudo pip3 install picusWindows> pip install picus## Example UsesPicus examples> picus -i input.csv -o output.json## Evidence Collection Process### PVS1
* PVS1 null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease.#### Status
* Implemented#### Resources
* LoF genes list from intervar.https://raw.githubusercontent.com/barslmn/InterVar/master/intervardb/PVS1.LOF.genes.hg19* Null variants defined as HIGH IMPACT byhttps://www.ensembl.org/info/genome/variation/prediction/predicted_data.html#### Conditions
* “gene_symbol” is in LoF gene list.
* “transcript_consequence_terms” is high impact.#### Shortcomings
* LoF gene list is only predictive and may be missing some actual LoF genes.
* No checks for multiexon deletion.### PS1
* Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.#### Status
* Implemented#### Resources
* Clinvar xml (ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/)#### Annotation Steps
1. Clinvar data is parsed usinghttps://github.com/barslmn/clinvar.
2. Sample data and clinvar data is merged based on columns “CHR” and “POS”.
3. Clinvar feature columns “ALT”, “hgvsp”, and “clinical_significance” added to original annotation.#### Conditions
1. “clinical_significance” is pathogenic.
2. Sample “hgvsp” and later added clinvar “hgvsp” changes are the same.
3. Sample “ALT” and clinvar “ALT” are different.#### Shortcomings### PS2
* De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.#### Status
* Not Checked#### Resources#### Conditions#### Shortcomings### PS3
* Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product#### Status
* Not Checked#### Resources#### Conditions#### Shortcomings### PS4
* The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls#### Status
* Implemented#### Resources
* Intervar#### Conditions
1. “id” is in id list.#### Shortcomings
1. No idea how the source is made.### PM1
* Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation#### Status
* Planned.#### Resources#### Conditions#### Shortcomings### PM2
* Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium#### Status
* Implemented#### Resources
* VEP#### Conditions
* “gnomad” less than 0.001.#### Shortcomings### PM3
* For recessive disorders, detected in trans with a pathogenic variant#### Status
* Planned for trio#### Resources#### Conditions#### Shortcomings### PM4
* Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants#### Status
* Implemented#### Resources
* VEP#### Conditions
* “transcript_consequence_terms” is “inframe_insertion”, “inframe_deletion”, or “stop_lost”.#### Shortcomings
* No checks for repeat regions.### PM5
* Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before#### Status
* Broken. (╯°□°）╯︵ ┻━┻)#### Resources
* Clinvar xml (ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/)#### Annotation Steps
1. Clinvar data is parsed usinghttps://github.com/barslmn/clinvar.
2. Sample data and clinvar data hgvsp columns parsed till position.
3. Synonym changes removed from clinvar data.
4. Clinvar feature columns “hgvsc”, and “clinical_significance” added to original annotation based on protein change position.#### Conditions
1. “gnomad” less then 0.001.
2. “clinical_significance” is pathogenic.
3. “transcript_consequence_terms” is missense variant.
4. “hgvsc” of the variant and clinvar entry dont match.#### Shortcomings### PM6
* Assumed de novo, but without confirmation of paternity and maternity#### Status
* Planned for trio.#### Resources#### Conditions#### Shortcomings### PP1
* Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease#### Status
* Planned after Vesta.#### Resources#### Conditions#### Shortcomings### PP2
* Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease#### Status
* Implemented#### Resources
* Intervar#### Conditions
* “transcript_consequence_terms” is a missense variant.
* “gene_symbol” is in PP2 gene list.#### Shortcomings### PP3
* Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)#### Status
* Implemented#### Resources
* Vep#### Conditions
* “sift_score” less than 0.05
* “polyphen_score” greater than 0.908#### Shortcomings### PP4
* Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology#### Status
* Not Checked.#### Resources#### Conditions#### Shortcomings### PP5
* Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation#### Status
* Implemented.#### Resources
* Clinvar#### Conditions
* “clinical_significance” is Pathogenic.#### Shortcomings### Benign### BA1
* Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium#### Status
* Implemented.#### Resources
* Vep#### Conditions
* “minor_allele_freq” is greater than 0.05OR“gnomad” is greater than 0.05.#### Shortcomings### BS1
* Allele frequency is greater than expected for disorder#### Status
* Planned for later.#### Resources#### Conditions#### Shortcomings### BS2
* Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age#### Status
* Planned#### Resources
* Intervar#### Conditions#### Shortcomings### BS3
* Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing#### Status
* Not Checked.#### Resources#### Conditions#### Shortcomings### BS4
* Lack of segregation in affected members of a family#### Status
* Not Checked.#### Resources#### Conditions#### Shortcomings### BP1
* Missense variant in a gene for which primarily truncating variants are known to cause disease#### Status
* Implemented.#### Resources
* Intervar#### Conditions
* “transcript_consequence_terms” is a missense variant.
* “gene_symbol” is in BP1 gene list.#### Shortcomings### BP2
* Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern#### Status
* Planned for trio.#### Resources#### Conditions#### Shortcomings### BP3
* In-frame deletions/insertions in a repetitive region without a known function#### Status
* Not Checked.#### Resources#### Conditions#### Shortcomings### BP4
* Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)#### Status
* Implemented#### Resources
* VEP#### Conditions
* “sift_score” greater than or equals to 0.05
* “polyphen_score” less than or equals to 0.446#### Shortcomings### BP5
* Variant found in a case with an alternate molecular basis for disease#### Status
* Not Checked.#### Resources#### Conditions#### Shortcomings### BP6
* Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation#### Status
* Implemented#### Resources
* Clinvar#### Conditions
* “clinical_significance” is benign#### Shortcomings### BP7
* A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved#### Status
* Planned#### Resources#### Conditions#### Shortcomings