clinvar数据库重新了解一下 / 四六文摘

在很久以前的我直播基因组活动，我提到过这个数据库：【直播】我的基因组67：clinvar数据库

不过，那个时候遗传背景知识不够，其实并没有很好的理解它，现在有机会重新学习一下，可以使用以下代码下载并且注释到clinvar数据库

wget https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/clinvar_20180429.vcf.gz wget https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/clinvar_20180429.vcf.gz.tbi java -jar ~/biosoft/SnpEff/snpEff/SnpSift.jar annotate clinvar_20180429.vcf.gz merge_snpeff.vcf >merge_clinvar.vcf

在其官网可以看到数据库更新还是蛮频繁的：

查看头文件的注释信息，描述是：

##SnpSiftCmd="SnpSift annotate clinvar_20180429.vcf.gz merge_snpeff.vcf" ##INFO=<ID=CLNDISDBINCL,Number=.,Type=String,Description="For included Variant: Tag-value pairs of disease database name and identifier, e.g. OMIM:NNNNNN"> ##INFO=<ID=DBVARID,Number=.,Type=String,Description="nsv accessions from dbVar for the variant"> ##INFO=<ID=CLNSIGCONF,Number=.,Type=String,Description="Conflicting clinical significance for this single variant"> ##INFO=<ID=AF_TGP,Number=1,Type=Float,Description="allele frequencies from TGP"> ##INFO=<ID=MC,Number=.,Type=String,Description="comma separated list of molecular consequence in the form of Sequence Ontology ID|molecular_consequence"> ##INFO=<ID=AF_EXAC,Number=1,Type=Float,Description="allele frequencies from ExAC"> ##INFO=<ID=CLNDN,Number=.,Type=String,Description="ClinVar's preferred disease name for the concept specified by disease identifiers in CLNDISDB"> ##INFO=<ID=ORIGIN,Number=.,Type=String,Description="Allele origin. One or more of the following values may be added: 0 - unknown; 1 - germline; 2 - somatic; 4 - inherited; 8 - paternal; 16 - maternal; 32 - de-novo; 64 - biparental; 128 - uniparental; 256 - not-tested; 512 - tested-inconclusive; 1073741824 - other"> ##INFO=<ID=CLNVI,Number=.,Type=String,Description="the variant's clinical sources reported as tag-value pairs of database and variant identifier"> ##INFO=<ID=CLNVC,Number=1,Type=String,Description="Variant type"> ##INFO=<ID=AF_ESP,Number=1,Type=Float,Description="allele frequencies from GO-ESP"> ##INFO=<ID=CLNHGVS,Number=.,Type=String,Description="Top-level (primary assembly, alt, or patch) HGVS expression."> ##INFO=<ID=CLNDNINCL,Number=.,Type=String,Description="For included Variant : ClinVar's preferred disease name for the concept specified by disease identifier s in CLNDISDB"> ##INFO=<ID=CLNVCSO,Number=1,Type=String,Description="Sequence Ontology id for variant type"> ##INFO=<ID=CLNSIG,Number=.,Type=String,Description="Clinical significance for this single variant"> ##INFO=<ID=CLNDISDB,Number=.,Type=String,Description="Tag-value pairs of disease database name and identifier, e.g. OMIM:NNNNNN"> ##INFO=<ID=CLNREVSTAT,Number=.,Type=String,Description="ClinVar review status for the Variation ID"> ##INFO=<ID=CLNSIGINCL,Number=.,Type=String,Description="Clinical significance for a haplotype or genotype that includes this variant. Reported as pairs of VariationID:clinical significance."> ##INFO=<ID=ALLELEID,Number=1,Type=Integer,Description="the ClinVar Allele ID">

记录最多的基因是

zcat clinvar_20180429.vcf.gz|perl -alne '{/GENEINFO=(.*?):/;print $1 if $1}'|sort |uniq -c |sort -k 1,1nr >gene.clinvar.freq head gene.clinvar.freq 9800 TTN 9038 BRCA2 6311 BRCA1 4987 ATM 4498 APC 3312 TSC2 3114 MSH6 2888 NF1 2653 MSH2 2223 LDLR

可以看到BRCA1/2遥遥领先呀！！！

记录的致病情况最多的基因是

zcat clinvar_20180429.vcf.gz|perl -alne '{/GENEINFO=(.*?):/;$g=$1;/CLNSIG=(.*?);/;print "$g\t$1" if $1}'| sort |uniq -c |sort -k 1,1nr >gene_sign.clinvar.freq head gene_sign.clinvar.freq 5218 TTN Uncertain_significance 3293 BRCA2 Uncertain_significance 2665 BRCA2 Pathogenic 2523 ATM Uncertain_significance 2162 BRCA1 Pathogenic 1897 APC Uncertain_significance 1887 TTN Likely_benign 1817 BRCA1 Uncertain_significance 1651 MSH6 Uncertain_significance 1465 BRCA2 Likely_benign grep Pathogenic gene_sign.clinvar.freq|head 2665 BRCA2 Pathogenic 2162 BRCA1 Pathogenic 691 LDLR Pathogenic 594 MSH2 Pathogenic 571 MLH1 Pathogenic 544 COL4A5 Pathogenic 536 NF1 Pathogenic 469 DMD Pathogenic 467 MSH6 Pathogenic 466 APC Pathogenic

仍然是BRCA1/2遥遥领，有趣的是TTN基因的致病位点压根就排不上号，其位点虽然在clinVar数据库收录多，但意义不明确，或者并不致病。

看看是否有被专家审核

zcat clinvar_20180429.vcf.gz|perl -alne '{/GENEINFO=(.*?):/;$g=$1;/CLNSIG=(.*?);/;$t=$1;/CLNREVSTAT=(.*?);/;print "$g\t$t\t$1" if $1}'| sort |uniq -c |sort -k 1,1nr >gene_sign_review.clinvar.freq [jianmingzeng@jade anno]$ head gene_sign_review.clinvar.freq 4200 TTN Uncertain_significance criteria_provided,_single_submitter 2065 BRCA2 Pathogenic reviewed_by_expert_panel 1915 BRCA2 Uncertain_significance criteria_provided,_single_submitter 1666 BRCA1 Pathogenic reviewed_by_expert_panel 1639 TTN Likely_benign criteria_provided,_single_submitter 1597 ATM Uncertain_significance criteria_provided,_single_submitter 1251 APC Uncertain_significance criteria_provided,_single_submitter 1200 TTN Conflicting_interpretations_of_pathogenicity criteria_provided,_conflicting_interpretations 1174 TSC2 not_provided no_assertion_provided

可以看到之前的Pathogenic的BRCA2突变记录是2665个，但是现在增加了 reviewed_by_expert_panel 条件后下降到了 2065个，还有600个是因为：

grep BRCA2 gene_sign_review.clinvar.freq|grep Pathogenic 2065 BRCA2 Pathogenic reviewed_by_expert_panel 436 BRCA2 Pathogenic criteria_provided,_single_submitter 94 BRCA2 Pathogenic criteria_provided,_multiple_submitters,_no_conflicts 70 BRCA2 Pathogenic no_assertion_criteria_provided

距离我写完这个教程，clinVar又更新了！！！！

使用annovar注释自己的vcf文件到clinVar数据库

annovar的安装及使用教程自行查看我在生信菜鸟团的博客或者生信技能树论坛分享的。

dir=/home/jianmingzeng/biosoft/ANNOVAR/annovar db=$dir/humandb/ ls $db


wget https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/archive_2.0/2018/clinvar_20180603.vcf.gz
perl $dir/annotate_variation.pl  --downdb --webfrom annovar --buildver hg38 

clinvar_20180603 $db

# perl $bin  --downdb --webfrom annovar --buildver hg38 gnomad_genome $db

mkdir annovar_results 

 $dir/convert2annovar.pl -format vcf4old highQ.vcf  1> highQ.avinput  2>/dev/null 

perl $dir/annotate_variation.pl  -buildver hg38 -filter -dbtype clinvar_20180603  --outfile annovar_results/highQ_clinvar  highQ.avinput  $db

perl $dir/table_annovar.pl \ -buildver hg38 \ highQ.avinput $db \ -out test \ -remove -protocol \ refGene,clinvar_20170905 \ -operation g,r \ -nastring NA

注释结果如下：

981K Aug 13 16:52 highQ_clinvar.hg38_clinvar_20180603_dropped 11M Aug 13 16:52 highQ_clinvar.hg38_clinvar_20180603_filtered 105K Aug 13 16:52 highQ_clinvar.invalid_input 1.1K Aug 13 16:52 highQ_clinvar.log

然后我发现 clinvar_20180603 这个版本的数据库其实是有问题的。

有趣的是使用annovar下载的clinVar数据库与其NCBI官网的文件对snp的书写方式其实是不一样的.

比如官网下载文件如下：

13 32340301 266906 TG T . . ALLELEID=261321;CLNDISDB=MedGen:C2675520,OMIM:612555;CLNDN=Breast-ovarian_cancer,_familial_2;CLNHGVS=NC_000013.11:g.32340303delG;CLNREVSTAT=reviewed_by_expert_panel;CLNSIG=Pathogenic;CLNVC=Deletion;CLNVCSO=SO:0000159;GENEINFO=BRCA2:675;MC=SO:0001589|frameshift_variant;ORIGIN=1;RS=886040621

但是annovar下载的如下:

clinvar数据库重新了解一下

记录最多的基因是

记录的致病情况最多的基因是

看看是否有被专家审核

使用annovar注释自己的vcf文件到clinVar数据库

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