The American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) updated their guidelines for the classification and reporting of copy number variations (CNVs) identified through next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) technologies in 2019 (Rigges et. al). The updated recommendations are divided into five main evidence criteria/sections, each with a set of rules that assign a default recommended score to a case when the rule is met. However, the guidelines allow for the score to be upgraded or downgraded based on the specific case.
After all evidence rules are evaluated, the final score is accumulated from all the evidence scores, and the final classification is determined based on the following score ranges:
Score > 0.99 => Pathogenic
Score [0.9,0.99] => Likely pathogenic
Score [-0.9,0.9] => VUS
Score [-0.9, -0.9-] => Likely benign
Score < -0.99 => Benign
Section One: Contains protein-coding or other known functionally important elements
Section one checks whether a functional element such as a gene or dosage-sensitive region exists in that region or not
Section Two: Overlap with Established\Predicted Region
The most complex section for calculation is section two, which involves evaluating the overlap of the variant with dosage-sensitive or benign genes/regions. This section takes into account Franklin's dosage sensitivity assessment for each gene and region that the variant overlaps with, as well as the type of overlap and impact on each gene/region.
Franklin's dosage sensitivity assessment is derived from three sources: the ClinGen dosage sensitivity database, the number of reported P/LP loss of function variants in the gene, and internal curation for dosage sensitivity.
Franklin's dosage sensitivity assessment is derived from three sources:
ClinGen dosage sensitivity database
The number of reported P/LP loss of function variants in the gene (suggesting the variant is haploinsufficient or dosage sensitive).
Five or more variants suggest high evidence
Two-four variants suggest moderate evidence
One variant suggests low evidence
Internal curation for dosage sensitivity
Based on the level of evidence, it will receive a higher or lower score.
Section Three: Evaluation of Gene Number
Franklin automatically calculates the number of protein-coding genes, which are not from the same protein family, and applies the rules accordingly
Section Four: Evidence from Public and Internal Data
In section 4, in line with the guidelines, Franklin includes gnomAD's and DGV gold As per the guidelines, Franklin incorporates the gnomAD's and DGV gold frequency databases in section 4 and evaluates them based on the variant frequency and its overlap. Similarly, it applies the case-control rules based on the evidence derived from ClinVar and Decipher.
In addition, if additional information exists in the literature, the user can add it manually.
Section Five: Patient inheritance pattern or family history
In this section, manually added evidence can be included based on the segregation information of the case under analysis.
Important to notice, that Franklin's final classification is global and does not differentiate between recessive or dominant conditions, so clinical outcome determination should be based on the patient's zygosity.
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