CADD plugin not working as expected in v111

[puva]

Hi,
we recently upgraded VEP from v107 to v111 (executable, cache and plugins), and we found that some variants correctly annotated in v107, with v111 have the CADD scores only in some conditions.
An example of these variants is chr1 100660 A C:

Case 1 - 2500 variants, --pick => CADD missing
Input: VCF with ~2500 variants, option --pick
Command line:
vep --assembly GRCh38 --cache --dir_cache [PATH]/vep_111 --dir_plugins [PATH]/Plugins_111 --force_overwrite --format vcf --input_file in_full.vcf --offline --plugin CADD,snv=/cadd_1.6_hg38/whole_genome_SNVs.tsv.gz,indels=/cadd_1.6_hg38/gnomad.genomes.r3.0.indel.tsv.gz --vcf --out_vep111_full_pick.vcf --pick
Output:
chr1 100660 . A C 8.82 PASS [...];CSQ=C|intron_variant&non_coding_transcript_variant|MODIFIER||ENSG00000238009|Transcript|ENST00000477740|lncRNA||3/3||||||||||-1||||| [...]

Case 2 - 2500 variants, no --pick => CADD ok
Input: VCF with ~2500 variants, without --pick
Command line:
vep --assembly GRCh38 --cache --dir_cache [PATH]/vep_111 --dir_plugins [PATH]/Plugins_111 --force_overwrite --format vcf --input_file in_full.vcf --offline --plugin CADD,snv=/cadd_1.6_hg38/whole_genome_SNVs.tsv.gz,indels=/cadd_1.6_hg38/gnomad.genomes.r3.0.indel.tsv.gz --vcf --out_vep111_full.vcf
Output (CADD in bold):
chr1 100660 . A C 8.82 PASS [...];CSQ=C|intron_variant&non_coding_transcript_variant|MODIFIER||ENSG00000238009|Transcript|ENST00000466430|lncRNA||2/3||||||||||-1||||4.519|0.319874,C|intron_variant&non_coding_transcript_variant|MODIFIER||ENSG00000238009|Transcript|ENST00000477740|lncRNA||3/3||||||||||-1||||4.519|0.319874 [...]

Case 3 - single variant, --pick => CADD ok
Input: VCF with chr1 100660 A C only, option --pick
Command line:
vep --assembly GRCh38 --cache --dir_cache [PATH]/vep_111 --dir_plugins [PATH]/Plugins_111 --force_overwrite --format vcf --input_file in_single.vcf --offline --plugin CADD,snv=/cadd_1.6_hg38/whole_genome_SNVs.tsv.gz,indels=/cadd_1.6_hg38/gnomad.genomes.r3.0.indel.tsv.gz --vcf --out_vep111_single.vcf --pick
Output (CADD in bold):
chr1 100660 . A C 8.82 PASS [...];CSQ=C|intron_variant&non_coding_transcript_variant|MODIFIER||ENSG00000238009|Transcript|ENST00000477740|lncRNA||3/3||||||||||-1||||4.519|0.319874 [...]

The same input files are correcly annotated with VEP 107 (executable, cache and plugins).
I tried using executable and cache from VEP 111 + CADD plugin from v107 and all variants were annotated.
It seems like a problem with the latest CADD plugin.

I'm attaching input and output files.
cadd_debug.tar.gz

Best,
Paolo

[olaaustine]

Hi @puva,
Thank you for your query and for the detailed information
We have been able to recreate the issue.
We will update this ticket when a fix has been applied.
Thank you very much
Ola.