owencqueen/cgbench_data huggingface dataset:
Gene: CDKL5 (HGNC:11411)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




Use as defined by ClinGen SVI working group (PMID:30192042).


PVS1 is applicable for:


Null variants up to p.R948 
when using the major brain isoform which has an alternative C-terminus (NM_001323289.2)


Frameshift variants that result in a read-through of the stop codon


Canonical splice site variants predicted to result in an out-of-frame product


Canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13) and for the non-coding CDKL5 exon (exon 1) 
(NM_001323289.2).


In-frame deletions including the PM1 functional domains (p.V19_K43 ATP binding domain or p.T169_Y171 TEY phosphorylation domain)


Deletions and duplications ≥1 exon in size (that are completely contained within the CDKL5 gene) where the reading frame is disrupted and NMD is predicted to occur


A full gene deletion
Gene: CDKL5 (HGNC:11411)
Evidence Code: PVS1 — Strong
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Strong is applicable for:


Cannonical splice site variants that flank exon 18 
(the final exon of NM_001323289.2)


Single to multi exon deletions that disrupt the reading frame such that exon 18 
(the final exon of NM_001323289.2)
 is truncated/altered


Duplications ≥1 exon in size (that are completely contained within the CDKL5 gene) where the reading frame is presumed to be disrupted and NMD is predicted to occur
Gene: CDKL5 (HGNC:11411)
Evidence Code: PVS1 — Moderate
Modification Type: Disease-specific,Strength
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Moderate is applicable for:


Any truncating variant distal of p.R948 (
when using the major brain isoform, NM_001323289.2
)


Canonical splice site variants that flank exon 17 (in-frame exon) (
NM_001323289.2
)
Gene: CDKL5 (HGNC:11411)
Evidence Code: PVS1 — Supporting
Modification Type: Disease-specific,Strength
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Supporting is applicable for initiation codon variants in 
CDKL5.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PS2 — Strong
Modification Type: None
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.




1 occurrence of PS2.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PM4 — Moderate
Modification Type: Disease-specific
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.




Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.P904) 
(when using the NM_003159.2 transcript)
.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).




For missense variants use REVEL with a score ≥ 0.644.


For splice site variants use SpliceAI with a score ≥ 0.2.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.




RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.


Not applicable for other functional studies.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP3 — Supporting
Modification Type: None
In-frame deletions/insertions in a repetitive region without a known function. 




BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP4 — Supporting
Modification Type: General recommendation
For missense variants use REVEL with a score ≤ 0.290.


For splice site variants use SpliceAI with a score ≤ 0.1.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP7 — Supporting
Modification Type: None
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.




Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.


For splice site variants use SpliceAI with a score ≤ 0.1.