-
Notifications
You must be signed in to change notification settings - Fork 54
New issue
Have a question about this project? Sign up for a free GitHub account to open an issue and contact its maintainers and the community.
By clicking “Sign up for GitHub”, you agree to our terms of service and privacy statement. We’ll occasionally send you account related emails.
Already on GitHub? Sign in to your account
Replace ClinVar whitelist with optional ClinVar-based scoring #515
Comments
Sounds like a good idea. I guess we could produce a new whitelist file
along these lines for all 2* variants
chr pos ref alt clinvar_category override_variant_score
var1 P 1
var2 LP 0.95
var3 VUS -
var 4 LB 0.05
var5 B 0
So for P, LP, LB and B override the usual variant score with these values
based on clinvar evidence. For VUS just rely on the Exomiser variant score.
Need to think if we want to whitelist LB and B variants that would
otherwise be filtered out - I think no, otherwise we will be swamped by
loads of common variants.
…On Wed, Sep 6, 2023 at 8:45 PM Jules Jacobsen ***@***.***> wrote:
The ClinVar whitelist option (default = true) will set all P/LP 2*+
variants found in a VCF file to have a score of 1.0.
The issue with this is that, while it works well for pathogenic variants,
it is useless for benign variants.
Another issue is that there is no longer a distinction between P and LP.
The ACMG guidelines state that there should be a >=0.99 for P and 0.90-0.98
probability of pathogenicity for these categories and a similar range for
B/LB.
Converting these probabilities to variant scores which override the
default implementation will allow us to keep the boost to the known
pathogenic variants and also de-prioritise known benign variants, some of
which would otherwise score rather highly.
The implementation issue here is should this be an optional setting which
can be set to false for use in internal benchmarks or would this be a case
of YAGNI. Also, how would this interact with the whitelist implementation?
Would this need to be updated so that the variants on the list should be
given a P/LP/LB/B label?
—
Reply to this email directly, view it on GitHub
<#515>, or unsubscribe
<https://github.com/notifications/unsubscribe-auth/ABHO4PA2JNGNBXQYWETPMYTXZDHERANCNFSM6AAAAAA4N2UYNU>
.
You are receiving this because you are subscribed to this thread.Message
ID: ***@***.***>
|
julesjacobsen
changed the title
Add optional ClinVar-based scoring
Replace ClinVar whitelist with optional ClinVar-based scoring
Sep 8, 2023
Yes, that's the idea. There are these issues to address:
The (now inaccurately named) whitelist can still be toggled on and off using the |
Sign up for free
to join this conversation on GitHub.
Already have an account?
Sign in to comment
The ClinVar whitelist option (default = true) will set all P/LP 2*+ variants found in a VCF file to have a score of 1.0.
The issue with this is that, while it works well for pathogenic variants, it is useless for benign variants.
Another issue is that there is no longer a distinction between P and LP. The ACMG guidelines state that there should be a >=0.99 for P and 0.90-0.98 probability of pathogenicity for these categories and a similar range for B/LB.
Converting these probabilities to variant scores which override the default implementation will allow us to keep the boost to the known pathogenic variants and also de-prioritise known benign variants, some of which would otherwise score rather highly.
The implementation issue here is should this be an optional setting which can be set to false for use in internal benchmarks or would this be a case of YAGNI? Also, how would this interact with the whitelist implementation? Would this need to be updated so that the variants on the list should be given a P/LP/LB/B label?
The text was updated successfully, but these errors were encountered: