owencqueen/cgbench_data huggingface dataset:
Gene: GCK (HGNC:4195)
Evidence Code: PVS1 — Original ACMG Summary
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Caveats:
 • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
 • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
 • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
 • Use caution in the presence of multiple transcripts.
Gene: GCK (HGNC:4195)
Evidence Code: PVS1 — Very Strong
Modification Type: Gene-specific
Use 
GCK
 PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group
1




Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD
2
. The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding.  Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.


“Exon skipping or  “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 


single exon deletions 


deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 


deletions of single 
exons 2,3,6 and 7
 cause frameshift --> 
PVS1
 


deletions or skipping of 
exons 8 and 9
 are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> 
PVS1
 


deletions or skipping of 
exons 4 and 5
 are in-frame and the proportion is <10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180
3
 according to Beck et al., Biochemistry 2013/ --> 
PVS1
 


deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10  --> 
PVS1










Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 


Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.
Gene: GCK (HGNC:4195)
Evidence Code: PVS1 — Strong
Modification Type: Strength
Use 
GCK
 PVS1 decision tree.


Per the SVI standard PVS1 decision tree, apply PVS1_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur.
Gene: GCK (HGNC:4195)
Evidence Code: PVS1 — Supporting
Modification Type: Strength
Use 
GCK
 PVS1 decision tree.




Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 


Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.
Gene: GCK (HGNC:4195)
Evidence Code: PS1 — Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: GCK (HGNC:4195)
Evidence Code: PS1 — Strong
Modification Type: None
No change
Gene: GCK (HGNC:4195)
Evidence Code: PS1 — Supporting
Modification Type: Strength
PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.
Gene: GCK (HGNC:4195)
Evidence Code: PS2 — Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: GCK (HGNC:4195)
Evidence Code: PS2 — Very Strong
Modification Type: Gene-specific,Strength
Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
.
Gene: GCK (HGNC:4195)
Evidence Code: PS2 — Strong
Modification Type: Gene-specific,Strength
Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
Gene: GCK (HGNC:4195)
Evidence Code: PS2 — Moderate
Modification Type: Gene-specific,Strength
Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
Gene: GCK (HGNC:4195)
Evidence Code: PS2 — Supporting
Modification Type: Gene-specific,Strength
Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
Gene: GCK (HGNC:4195)
Evidence Code: PS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
Gene: GCK (HGNC:4195)
Evidence Code: PS3 — Strong
Modification Type: Gene-specific,Strength
Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.
Gene: GCK (HGNC:4195)
Evidence Code: PS3 — Moderate
Modification Type: Gene-specific,Strength
See list of approved functional studies and guidelines for interpretation of data.
Gene: GCK (HGNC:4195)
Evidence Code: PS3 — Supporting
Modification Type: Gene-specific,Strength
See list of approved functional studies and guidelines for interpretation of data (below).
Gene: GCK (HGNC:4195)
Evidence Code: PS4 — Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
Gene: GCK (HGNC:4195)
Evidence Code: PS4 — Strong
Modification Type: Gene-specific,Strength
7 or more occurrences in unrelated individuals = Strong.
Gene: GCK (HGNC:4195)
Evidence Code: PS4 — Moderate
Modification Type: Gene-specific,Strength
4-6 occurrences in unrelated individuals = Moderate.
Gene: GCK (HGNC:4195)
Evidence Code: PM1 — Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Gene: GCK (HGNC:4195)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific
Applicable for glucose- and ATP-binding sites (see attached chart).
Gene: GCK (HGNC:4195)
Evidence Code: PM2 — Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Caveat: Population data for indels may be poorly called by next generation sequencing.
Gene: GCK (HGNC:4195)
Evidence Code: PM2 — Supporting
Modification Type: Gene-specific
gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.
Gene: GCK (HGNC:4195)
Evidence Code: PM3 — Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
Gene: GCK (HGNC:4195)
Evidence Code: PM3 — Very Strong
Modification Type: Strength
Use SVI-recommended point-based system.
Gene: GCK (HGNC:4195)
Evidence Code: PM3 — Strong
Modification Type: Strength
Use SVI-recommended point-based system.
Gene: GCK (HGNC:4195)
Evidence Code: PM3 — Moderate
Modification Type: Strength
Use SVI-recommended point-based system.
Gene: GCK (HGNC:4195)
Evidence Code: PM3 — Supporting
Modification Type: Strength
Use SVI-recommended point-based system.
Gene: GCK (HGNC:4195)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: GCK (HGNC:4195)
Evidence Code: PM4 — Moderate
Modification Type: Strength
For single amino acid deletions, use as supporting level of evidence.
Gene: GCK (HGNC:4195)
Evidence Code: PM4 — Supporting
Modification Type: Strength
For single amino acid deletions/insertions, use as supporting level of evidence
Gene: GCK (HGNC:4195)
Evidence Code: PM5 — Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Example: Arg156His is pathogenic; now you observe Arg156Cys.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: GCK (HGNC:4195)
Evidence Code: PM5 — Strong
Modification Type: Strength
Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.
Gene: GCK (HGNC:4195)
Evidence Code: PM5 — Moderate
Modification Type: Strength
The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.
Gene: GCK (HGNC:4195)
Evidence Code: PM5 — Supporting
Modification Type: Strength
Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.
Gene: GCK (HGNC:4195)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: GCK (HGNC:4195)
Evidence Code: PP1 — Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Note: May be used as stronger evidence with increasing segregation data.
Gene: GCK (HGNC:4195)
Evidence Code: PP1 — Strong
Modification Type: General recommendation,Gene-specific
Use thresholds suggested by Jarvik and Browning
8




Single Family : ≤ 1/32 (5 meioses)


>1 Family : ≤ 1/16 (4 meioses)
Gene: GCK (HGNC:4195)
Evidence Code: PP1 — Moderate
Modification Type: General recommendation,Gene-specific
Use thresholds suggested by Jarvik and Browning
8




Single Family : ≤ 1/16 (4 meioses)


>1 Family : ≤ 1/8 (3 meioses)
Gene: GCK (HGNC:4195)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation,Gene-specific
Use thresholds suggested by Jarvik and Browning
8




Single Family : ≤ 1/8 (3 meioses)


>1 Family : ≤ ¼ (2 meioses)
Gene: GCK (HGNC:4195)
Evidence Code: PP2 — Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Gene: GCK (HGNC:4195)
Evidence Code: PP2 — Supporting
Modification Type: Gene-specific
Apply to all missense variants in GCK. gnomAD missense constraint score for 
GCK
 is 3.07 (observed/expected= 0.5), which is significant.
Gene: GCK (HGNC:4195)
Evidence Code: PP3 — Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
Gene: GCK (HGNC:4195)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation
Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2
9
,
10
Gene: GCK (HGNC:4195)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: GCK (HGNC:4195)
Evidence Code: PP4 — Moderate
Modification Type: Gene-specific,Strength
HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:




PP4 phenotype found in pediatric patient (prepubertal or <10 years) (incidentally) AND 


Not treated with insulin AND antibody negative 


OR treated with insulin, antibody negative, and detectable C-peptide (> 0.6ng/mL) after 3 years






Multiple values (= persistent)—multiple levels (>=2 counts) or well-documented persistent impaired fasting glucose (IFG) 


OGTT with minimal increment <3 mmol/l (54 mg/dl) 


Antibody negative 


Macrosomia in normoglycemic offspring of hyperglycemic gestational parent


Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. 


Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)
Gene: GCK (HGNC:4195)
Evidence Code: PP4 — Supporting
Modification Type: Gene-specific
HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL)
Gene: GCK (HGNC:4195)
Evidence Code: PP5 — Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: GCK (HGNC:4195)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: GCK (HGNC:4195)
Evidence Code: BA1 — Stand Alone
Modification Type: Gene-specific
gnomAD 2.1.1 Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).
Gene: GCK (HGNC:4195)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: GCK (HGNC:4195)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
gnomAD 2.1.1 Popmax Filtering AF ≥ 1:25,000 (0.004% or 0.00004).
Gene: GCK (HGNC:4195)
Evidence Code: BS2 — Original ACMG Summary
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Gene: GCK (HGNC:4195)
Evidence Code: BS2 — Strong
Modification Type: Gene-specific
We expect to see hyperglycemia at birth in an individual with _GCK_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood.  Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (<100 mg/dl / 5.6 mmol/L).
Gene: GCK (HGNC:4195)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: GCK (HGNC:4195)
Evidence Code: BS3 — Strong
Modification Type: Gene-specific
Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4).
Gene: GCK (HGNC:4195)
Evidence Code: BS3 — Supporting
Modification Type: Gene-specific
Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.


Evidence of no impact on function:




Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3_Supporting 


Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3




Gloyn, et al. 2005 
5
; Beer, et al. 2012 
6
; Raimondo, et al. 2014 
7
; Gloyn, et al. (2004)
12
.
Gene: GCK (HGNC:4195)
Evidence Code: BS4 — Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.
Gene: GCK (HGNC:4195)
Evidence Code: BS4 — Strong
Modification Type: Gene-specific
Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))
Gene: GCK (HGNC:4195)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: GCK (HGNC:4195)
Evidence Code: BP2 — Original ACMG Summary
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Gene: GCK (HGNC:4195)
Evidence Code: BP2 — Supporting
Modification Type: General recommendation
Also applicable when in cis or trans with a likely pathogenic variant.
Gene: GCK (HGNC:4195)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: GCK (HGNC:4195)
Evidence Code: BP4 — Original ACMG Summary
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
Gene: GCK (HGNC:4195)
Evidence Code: BP4 — Supporting
Modification Type: General recommendation
Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
9
,
10
.
Gene: GCK (HGNC:4195)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: GCK (HGNC:4195)
Evidence Code: BP5 — Supporting
Modification Type: General recommendation
A variant in another monogenic diabetes gene is P/LP.
Gene: GCK (HGNC:4195)
Evidence Code: BP6 — Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: GCK (HGNC:4195)
Evidence Code: BP7 — Original ACMG Summary
A synonymous 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.
Gene: GCK (HGNC:4195)
Evidence Code: BP7 — Supporting
Modification Type: Gene-specific
Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.