Our previous webcast demonstrated some of the new functionalities of VSClinical, including the ability to add ACMG frequency sources for the ACMG BA1, BS1, and PM2 criteria. This new feature was spurred by the feedback from our users, which requested supporting frequency tracks other than gnomAD Exomes and 1kG Phase3. Now, users can implement population catalogs to VSClinical such as TopMed, KAVIAR, UK-Twins, and dbGAP as well as internal population databases as long as they have a minimum of 2,000 samples.
When the population databases have been added, they can then be visualized in the VSClinical interface. As shown in Figure 2, the user now can toggle between the frequency tracks and observe the highest frequency among the individual subpopulations and see if the variant in question occurs in a homozygous genotype state. Furthermore, the PM2 criteria recommendation is now based on a very low allele frequency instead of an absolute total allele count to be more robust to population catalogs with small sample sizes. In rare cases, the previous behavior resulted in both PM2 and BA1 being recommended. These settings are tunable, but by default, the PM2 threshold is less than 0.02% for recessive genes and 0.01% for dominant genes. The threshold will be evaluated on the sub-population with the largest allele frequency that meets the specified minimum allele count.
In addition, the evidence of the frequency tracks will also be applied to the ACMG scoring criteria. As shown in Figure 3, the auto recommendation will incorporate the findings from the other frequency databases, which will allow for a more balanced interpretation of the variant in question. In this situation, the variant is observed at a low frequency in gnomAD and KAVIAR but is novel in the other custom frequency tracks. Thus, we can answer Yes to PM2, which states that the variant is absent from controls in population catalogs.
Lastly, the evidence from these frequency tracks will be automatically incorporated into your assessment catalog, which can then be rendered into a clinical report. As shown in Figure 3, the frequency information of the variant according to gnomAD, TopMed, KAVIAR, UK-Twins, and dbGAP is listed in the final interpretation of the variant.
Together, the updated VSClinical interface contains a large volume of new content. In this blog, we covered adding additional population tracks to further the evaluation of the ACMG criteria BA1, BS1, and PM2 and how this information is automatically incorporated into the assessment catalog and clinical report. I hope this gives you a little more insight into some of the new features of adding population catalogs to VSClinical but if you have any questions or would like to have a demonstration of the software, feel free to reach out to email@example.com. Feel free to check out some of our other blogs that always contain important news and updates for the next-gen sequencing community.