owencqueen/cgbench_data huggingface dataset:
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PVS1 — Very Strong
Modification Type: None
Loss of function is a known mechanism of disease for Creatine Transporter Deficiency.


Specifications are based on the decision tree as outlined in Tayoun etal, 2018 (Hum Mutat. 2018 Nov;39(11):1517-1524; PMID: 30192042) SLC6A8: PVS1 is applicable as described in Abou Tayoun et al, 2018 (PMID: 30192042)
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS2 — Strong
Modification Type: None
Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS2 — Moderate
Modification Type: Strength,Disease-specific
Newly hemizygous male with variant identified in mother.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
RT-PCR evidence of mis-splicing for non-canonical intronic variants
For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS4 — Supporting
Modification Type: Strength
One independent male proband in addition to any proband used for PP4.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific
Absent/rare from controls in an ethnically-matched cohort population sample.
Threshold: <0.00002 (0.002%) AND 0 hemizygotes in gnomAD.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP4 — Strong
Modification Type: Disease-specific
See points scheme in main document


4 or more points are required for PP4_Strong; two or more data types must be available to apply PP4_Strong, full sequencing of SLC6A8, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.




For PP4, assign points for each type of data present, and then add up the points.




PP4 = 1-2 points, PP4_Moderate = 3 points, PP4_Strong = 4 points


Two or more data types are recommended to reach moderate and required to reach strong.


An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.


Variant must meet PM2_Supporting for PP4 to apply at any strength.


For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP4 — Moderate
Modification Type: Strength
See points scheme in main document.


3 points required for PP4_Moderate.




For PP4, assign points for each type of data present, and then add up the points.




PP4 = 1-2 points, PP4_Moderate = 3 points, PP4_Strong = 4 points


Two or more data types are recommended to reach moderate and required to reach strong.


An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.


Variant must meet PM2_Supporting for PP4 to apply at any strength.


For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Elevated urine creatine/creatinine ratio.
• 1-2 points required for PP4; at minimum, elevated urine creatine/creatinine level on one occasion.




For PP4, assign points for each type of data present, and then add up the points.




PP4 = 1-2 points, PP4_Moderate = 3 points, PP4_Strong = 4 points


Two or more data types are recommended to reach moderate and required to reach strong.


An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.


Variant must meet PM2_Supporting for PP4 to apply at any strength.


For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: BS3 — Supporting
Modification Type: Strength,Disease-specific
Creatine transport assay demonstrating ≥50% normal transport activity using physiological creatine concentrations (≤125μM creatine).


RT-PCR evidence demonstrating no observable effect of splicing.


Expression assay demonstrating wild type transcript levels