This week many new tracks were added to the NxClinical track auto-update system. Below is a detailed description of what was added.
CIViC – CIViC is an open access, open source, community-driven web resource for Clinical Interpretation of Variants in Cancer. Variants include SNV, insertion/deletion, CNV, structural variants, transcript fusions and other events with cancer associations that have some evidence of clinical relevance. CIViC contains somatic variants, germline variants, and common polymorphisms related to cancer, however, most variants in CIViC are somatic mutations. A manuscript describing CIViC has been published in Nature Genetics.
The ClinGen Curated Dosage Sensitivity Map (database nstd45) tracks -
A number of new tracks have been added representing this data set. The ClinGen Curated Dosage Sensitivity Map represents curated regions of the genome, including genes and genomic regions that are believed to be dosage sensitive after evidence-based literature review. The genes and genomic regions submitted to the database are those with sufficient evidence supporting (pathogenic) or refuting (benign) dosage sensitivity (i.e. haploinsufficieny or triplosensitivity) as a mechanism for disease. Haploinsufficiency is a state where a diploid organism with only a single functional copy of a gene results in insufficient production of the product leading to an abnormal or diseased state. Triplosensitivity is the converse whereby an extra copy of the gene (three copies total) leads to an abnormal state. Evidence is evaluated on a continual basis by the ClinGen Structural Variation Working Group as described in Riggs et al. 2012.
The ClinGen Curated Dosage Sensitivity Map tracks now include several tracks split up by genes and regions, pathogenic/benign, as well as by dosage sensitivity (haploinsufficiency/triplosensitivity) as listed below. These tracks are especially useful in the decision tree (Variant Interpretation Assistance system in NxClinical) that applies rules to pre-classify events based on several criteria including events falling into the following categories:
ClinGen Curated Dosage Sensitivity Map Benign Genes
ClinGen Curated Dosage Sensitivity Map Pathogenic Genes
ClinGen Curated Dosage Sensitivity Map Benign Regions
ClinGen Curated Dosage Sensitivity Map Pathogenic Regions
ClinGen Dosage Sensitive Map Haploinsufficiency Benign Genes
ClinGen Dosage Sensitive Map Haploinsufficiency Pathogenic Genes
ClinGen Dosage Sensitive Map Haploinsufficiency Benign Regions
ClinGen Dosage Sensitive Map Haploinsufficiency Pathogenic Regions
ClinGen Dosage Sensitive Map Triplosensitivity Benign Genes
ClinGen Dosage Sensitive Map Triplosensitivity Pathogenic Genes
ClinGen Dosage Sensitive Map Triplosensitivity Benign Regions
ClinGen Dosage Sensitive Map Triplosensitivity Pathogenic Regions
The Development Disorder Genotype - Phenotype Database (DDG2P) tracks - The DDG2P db is a curated list of genes reported to be associated with developmental disorders, compiled by clinicians as part of the Deciphering Developmental Disorders (DDD) study to facilitate clinical feedback of likely causal variants. The DDG2P is categorized into the level of certainty that the gene causes developmental disease (confirmed or probable), the consequence of a mutation (loss-of function, activating, etc.) and the allelic status (monoallelic, biallelic) associated with disease. New tracks in NxClinical are split up into the following lists:
DECIPHER DDG2P Biallelic Confirmed
DECIPHER DDG2P Monoallelic Confirmed
DECIPHER DDG2P Monoallelic Unconfirmed
Imprinted Genes - This is a curated list of human gene names, status (predicted or imprinted) and the expressed allele (maternal, paternal or biallelic) from Gene Imprint.
Segmental Duplications - Obtained from UCSC. This contains a summary of large genomic duplications >1kb >90% similar. For a region to be included in the track, at least 1 Kb of the total sequence (containing at least 500 bp of non-RepeatMasked sequence) had to align and a sequence identity of at least 90% was required.