Good afternoon.
We will go ahead and get started with the Finding All Variants with ClinVar webinar.
Thank you for coming.
Please subscribe to our YouTube channel and tell your friends.
The purpose of this webinar obviously is to show you guys how to find all variants with
ClinVar.
The nice thing here, in either the NCBI homepage or in ClinVar, you can search for either disease
or phenotypes, gene names, or HGVS.
We're going to start by searching for phenotype and here I've searched for cardiomyopathy.
This is just from the NCBI homepage and I will get lots of different hits with lots
of different things.
For ClinVar there are tons of hits for asserted phenotypic variants linked to cardiomyopathy.
If I go in to ClinVar, and dig a little further I will see that I can facet these 7075 hits
that I get over here on the left.
These are all related to cardiomyopathy because that is what I searched for.
The first thing I could search for is what phenotypic assertion is.
Do they say this is pathogenic, a risk factor, benign?
For the purposes of this demonstration we are going to select the pathogenic one.
Now we can see that the asserted clinical significance is all pathogenic.
Now, what ClinVar does is aggregate these phenotypic assertions.
We consider this to be more trustworthy when multiple independent submitters have made
the same assertion.
Here we are going to pick the ones that have been made by multiple independent submitters.
And then we might also be interested in what the molecular consequence of his variants
are.
We can see that we have some that are frameshifts, missense, nonsense, and for the purposes of
this demonstration we'll choose the missense one.
Now we see a whole bunch of genes here.
We can also see in the display we get the HGVS notation.
Just to show you I can search by the HGVS notation, and I don't need the gene name,
I can use the standard notation.
And if I did that this would take me to a specific ClinVar page.
And this is what a specific ClinVar page looks like and if we dig down I would like to also
point out it is cross-referenced to the dbSNP as well as the 1000 genomes browser and these
two stars show it has been submitted by multiple submitters.
Once again, we can also search by gene and if we click on one of these gene symbols,
say, LMNA, it will take us to the Gene page for that particular gene.
And I can see a whole bunch of the isoforms down here in the sequence viewer.
If I scroll down in the same page I can see is that underneath the isoforms I get a whole
bunch of ClinVar variants and also other information down here which is really cool and will be
the subject of another webinar.
Anyway, I see the ClinVar variants and I say am interested in one of the last exon, I can
use the range tool tip to go ahead and zoom in on the last part of the gene.
Then I can mouse over one of those ClinVar purple boxes in order to show the variants
in that particular region of that particular exon.
There is another way I can do this and that is by going to NCBI variation viewer, the
easiest way in my opinion to find the viewer is to google NCBI variation viewer.
Once again, we can enter a location, a gene name or phenotype and we can find a particular
gene.
Let's say we search for Lamin A, it will display the gene symbol for lamin A, and if we click
on the blue arrow it will display the gene for Lamin A.
We can configure the display to show only isoforms, but we can also select one of the
last exons in this gene, zoom in, and then we can see in the zoomed version the ClinVar
variants.
By the way if you're interested in the variation viewer here is a link to the full-length variation
viewer webinar.
I will give you a couple of seconds to copy that down.
Also you can get there from the NCBI YouTube channel.
If we scroll down on the same page and variation viewer we can filter these variants by a whole
bunch of different things.
We can filter the only ones that are in ClinVar, the ones that are in dbSNP or dbVar, that
is, either under or over 50 nucleotides, the ones asserted as pathogenic or likely pathogenic
by ClinVar submitters, as well as the variant type and molecular consequence as we discussed
earlier.
When I go ahead and filter by these things I can look at the pathogenic, the asserted
to be pathogenic variants, just in this particular exon.
The nice thing as well as I can see for each of these particular variants how many publications
in PubMed support those particular assertions.
Back up to the top I can see the three pathogenic variants in this exon by looking at the purple
color of those particular variants here.
In fact, the different colors correspond to different phenotypic assertions.
I can also upload my own data into variation viewer and that is covered more specifically
in that variation viewer webinar that I had mentioned.
Finally I wanted to talk about batch download for ClinVar.
Really the easiest way in my opinion to do that is to go to the FTP site.
So if you go to ClinVar, which can be found at this URL, www.ncbi.nlm.nih.gov/clinvar,
or just by googling ClinVar, there is a link that says go to the FTP site.
On the FTP site it is trivial to get VCFs of all of the ClinVar assertions or those
assertions in XML, depending on what you prefer to parse.
I would like to thank the people on this list, formatted as a PubMed query, for help putting
together this presentation.
I would be happy to take any questions from the audience if there are any.
I should also mention that I am here with Melissa Landrum, the group lead for the ClinVar
database, and she will also be able to answer any questions should there be any I cannot
easily answer.
This is an good question, is there a controlled vocabulary for conditions?
If so, where and what is it?
If not how are condition names to be searched?
I believe Melissa will answer this more eloquently to then I.
So I am going to pass the microphone to her.
Thank you, Ben.
So in ClinVar submitters can provide their condition to us in several ways.
You can use an OMIM number, an HPO ID, an Orphanet ID, a Concept ID from UMLS, so there
are several options.
If your condition name is not represented in any of the databases you can provide it
to us as your own term.
Once we receive all this information to ClinVar we use the MedGen database at NCBI.
MedGen is really an aggregator of condition information from many different sources, including
the ones I mentioned, OMIM, HPO, Orphanet, UMLS, and it also includes novel terms that
come in directly to ClinVar which are then available to be incorporated into UMLS as
well.
When you're searching in ClinVar you can search by any of those IDs but you can also search
on just the term like the example of cardiomyopathy.
All right, are there any other questions?
The slides will be available on the NCBI FTP site.
But there will be a convenient link on the NCBI webinar's page, and again this video
should be available on YouTube in the next week or two.
If you liked the video and thought it was informative, please tell your friends.
With that, unless there any other questions will go ahead and sign off.
We hope you enjoyed this week's NCBI minute.
We should either have a NCBI minute or a full-length webinar every week for the rest of the summer.
Have an excellent day.