Release Notes for nstd102 (ClinVar submitted variants) updated March, 2019

Study Page: https://www.ncbi.nlm.nih.gov/dbvar/studies/nstd102/

Overview

Growth of nstd102:

Date Updated	Number of Variant Calls	Number of Variant Regions	Explanation
May 2016	771	761
October 2016	767	757	Dropped 4 inactive calls and regions.
December 2016	766	756	Dropped 1 inactive call and region.
April 2017	765	755	Dropped 1 inactive call and region.
March 2019	56,928	55,147	Began importing variants from ClinVar XML. Preserved existing nstd102 accessions. Dropped inactive calls and and regions.

nstd102 now contains ClinVar variants that are also in other dbVar studies. They are matched by dbVar (nssv, essv) or ClinVar (SCVs) links:

Study Accession	Study Name	Calls matched by nstd102	Calls not matched by nstd102	Explanation
nstd37	ClinGen Laboratory-Submitted	33,048
nstd51	User submitted curated variants	213	18	ClinVar has only cytogenetic placements.
nstd101	ClinGen Kaminsky et al. 2011	3,796
nstd102	ClinVar submitted variants	740		NOTE: 25 nstd102 variant calls and 77 nstd102 variant regions were obsoleted because their SCVs were no longer current in ClinVar.
nstd103	LSDB submitted variants	130
nstd133	Redin et al. 2016		921	Variant types (Translocation, Complex) not currently loaded back to dbVar. ClinVar has only cytogenetic placements.
estd216	Kasak et al. 2015	751	10	ClinVar has dbSNP but no dbVar link. NOTE: Will be matched in next release.
estd228	Ansari et al. 2016	12
estd232	Blanco-Kelly et al. 2017	8
Total		38,728

Scope of nstd102

ClinVar Variants excluded

These ClinVar Variants were excluded from nstd102:

Reason for exclusion	Count	Explanation
type="single nucleotide variant"	571,120	These should be in scope for dbSNP.
have dbSNP links and not linked to dbVar	64,482	These are already in dbSNP.
have cytogenetic placements only in ClinVar	3,266	dbVar only loads genomic placements. NOTE: Some of these can be linked to dbVar variants with genomic placements, and may be loaded to dbVar later.
type="Variation"	410	May be loaded to dbVar later.
type="Microsatellite"	272	May be loaded to dbVar later.
type="Translocation"	240	May be loaded to dbVar later.
type="protein only"	98	May be loaded to dbVar later.
type="Complex"	56	These should be in scope for dbSNP.
type="fusion"	8	These should be in scope for dbSNP.
Total	639,952

New nstd102 Variants

Summary of the new nstd102 variants (not linked to dbVar or dbSNP) according to type and size. Note that some of the small variants may eventually be claimed by dbSNP and assigned rs numbers. When this happens they will be dropped from nstd102.

Variant Call type	Total new	< 50bp	> 50bp
copy number gain	9466		9466
copy number loss	12806	4	12802
deletion	5590	2787	2803
duplication	2153	923	1230
indel	555	521	34
insertion	414	413	1
inversion	146	139	7
TOTAL	31,130	4787	26,343

Experiments

Previously, there were 74 different experiments based on the original ClinVar submitters.

All nstd102 calls are now attributed to 1 single experiment, with methods="Multiple", and analysis="Multiple".

Variant Calls

The previous nstd102 calls were based on ClinVar RCVs. Calls in other dbVar studies with ClinVar links are based on ClinVar SCVs (submitted variants).

The new nstd102 variant calls are based on the unique combination of: ClinVar RCV + AlleleID. This means that nstd102 variant calls can now have multiple or conflicting values of clinical significance, phenotype, and origin.

NOTE:

740 existing variant call accessions from nstd102 were preserved.
25 nstd102 variant calls were obsoleted because their SCVs were no longer current in ClinVar.

Merging Calls

Changes in properties of the nstd102 calls will means that calls that were separate in other dbVar studies would be merged into a single call in nstd102.

The new defining properties for calls in nstd102 will be:

RCV
AlleleID (based on placement)

This means that calls in nstd102 will be less specific in terms of many properties compared to calls in other dbVar studies. For example:

Property of dbVar calls in other studies	Consequence of dropping property in nstd102
dbVar study	calls from nstd37 and nstd101 may be merged into a single call in nstd102
submitter site	calls from "ISCA site 1" and "ISCA site 10" may be merged into a single call in nstd102
experiment method, analysis, and platform	calls from "Sequencing" and "SNP array" may be merged into a single call in nstd102
sample	calls from sample "643448" and "736636" may be merged into a single call in nstd102
origin	calls from "biparental" and "de novo" may be merged into a single call in nstd102
clinical significance	calls from "Likely pathogenic" and "Pathogenic" may be merged into a single call in nstd102
phenotype	calls with different phenotypes may be merged into a single call in nstd102

Variant Call types

The ClinVar variant type values were converted to the lower-case values in dbVar.

Summary of nstd102 variant call types.

Variant call type	count
copy number gain	22848
copy number loss	23805
deletion	6651
duplication	2438
indel	620
insertion	419
inversion	147

After matching nstd102 calls to variants in other dbVar studies through dbVar links or SCVs, there are only a few discrepencies that will be investigated.

Number of calls	variant type in other study	variant type in nstd102
5	deletion	copy number loss
4	copy number loss	deletion
1	copy number loss	copy number gain
1	indel	deletion
1	complex substitution	duplication
1	deletion	Indel

Clinical Significance

The ClinVar clinical significance values were loaded to dbVar without any translation. The new identity of variant calls as RCV + Allele_ID introduced new "combined" values of clinical significance. Summary of nstd102 clinical significance.

clinical significance	count
Affects	3
Benign/Likely benign	197
Benign	21832
Conflicting interpretations of pathogenicity	59
Likely benign	4224
Likely pathogenic	2088
Pathogenic/Likely pathogenic	22
Pathogenic	12604
Uncertain significance	14779
association	8
conflicting data from submitters	209
drug response	23
not provided	861
other	2
protective	1
risk factor	16

After matching nstd102 calls to variants in other dbVar studies through dbVar links or SCVs, some nstd102 calls have combined values, as expected due to the new identity of variant calls:

Number of calls	clinical significance in other study	clinical significance in nstd102
1189	Benign Likely benign	Benign/Likely benign
738	Benign Likely benign Likely pathogenic Pathogenic Uncertain significance	conflicting data from submitters
264	Benign Likely benign Likely pathogenic Pathogenic Uncertain significance	Conflicting interpretations of pathogenicity
29	Likely pathogenic Pathogenic	Pathogenic/Likely pathogenic

After matching nstd102 calls to variants in other dbVar studies through dbVar links or SCVs, there are only a few discrepencies that will be investigated.

Number of calls	clinical significance in other study	clinical significance in nstd102
7	not_provided	Benign
4	Likely benign Likely pathogenic Pathogenic	Uncertain significance
1	Benign	Pathogenic
1	Likely pathogenic	Pathogenic

Origin

The lower-case values of origin in ClinVar were converted to mixed-case values in dbVar. The new identity of variant calls as RCV + Allele_ID introduced a new value of origin, "see ClinVar for details". Summary of nstd102 origin.

origin	count
biparental	37
de novo	1347
germline	10797
inherited	146
maternal	1804
not provided	20192
paternal	1175
see ClinVar for details	714
somatic	228
tested-inconclusive	18
unknown	20470

After matching nstd102 calls to variants in other dbVar studies through dbVar links or SCVs, some nstd102 calls have "see ClinVar for details", as expected due to the new identity of variant calls:

Number of calls

origin in other study

origin in nstd102

2235

biparental

de novo

germline

maternal

not provided

paternal

tested-inconclusive

see ClinVar for details

After matching nstd102 calls to variants in other dbVar studies through dbVar links or SCVs, there are only a few discrepencies that will be investigated.

Number of calls

origin in other study

origin in nstd102

3

not provided

de novo

unknown

1

de novo

germline

Links

Summary of links in nstd102. Note that nstd102 calls will link to ClinVar RCV's, whereas dbVar variants in other studies mostly linked to ClinVar SCV's.

External Database	Number of links
ClinGen	795
ClinVar (RCV)	56928
GeneReviews	4719
HP	6511
MeSH	678
MedGen	32972
OMIM	28379
Orphanet	6485
PubMed	31180
dbSNP	163
dbVar (sv and ssv)	61832

Placements

In cases where ClinVar variants contained multiple Sequence Locations, only the one indicated as being on the "current" assembly was loaded to nstd102. About half of the "current" placements were on GRCh37, half on GRCh38, and a few were on NCBI36.

ClinVar variants with only cytogenetic placements were not loaded.

After loading dbVar, the placements were then remapped to multiple assemblies: NCBI36, GRCh37, and GRCh38.

After matching nstd102 calls to variants in other dbVar studies through dbVar links or SCVs, there are only a few discrepencies that will be investigated.

Summary of variants in other studies matched to nstd102 calls with different placement values:

Study	Number of matched calls with different placements	Explanation
nstd37	22	ClinVar dropped redundant outer_start
nstd51	5	Off by a few bases likely due to independently converting original cytogenetic to genomic
nstd102	3	Off by a few bases. 1 is off by 200k.
estd216	62	dbVarQa has outers. ClinVar has exact start/stop.

Variant Regions

Variant regions in nstd102 were generated based on merging calls having the same placement.

NOTE:

755 existing variant region accessions from nstd102 were preserved.
77 nstd102 variant regions were obsoleted because they were tied to calls whose SCVs were no longer current in ClinVar.

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