Variant classification summary

NM_002168.2:c.374-10G>A

IDH2 · NP_002159.2:p.? · NM_002168.2

GRCh37: chr15:90631989 C>T · GRCh38: chr15:90088757 C>T

Gene: IDH2 Transcript: NM_002168.2

Final call

VUS

BP4 supporting

Variant details

Gene

IDH2

Transcript

NM_002168.2

Protein

NP_002159.2:p.?

gnomAD AF

3.0982120837706976e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): SpliceAI max delta 0.003, well below the 0.1 threshold, predicts no splice impact.

2

VUS: with only BP4 (supporting) met under the generic ACMG/AMP 2015 combination rules, the evidence is insufficient to classify this variant as pathogenic or benign.

Final determination: A single BP4 (supporting) alone does not meet any Benign, Likely Benign, Likely Pathogenic, or Pathogenic combination threshold under generic ACMG/AMP 2015 rules, so the variant is classified as VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: deep intronic variant (10 bp upstream of exon 4) is not a canonical splice-site or null variant, and SpliceAI max delta 0.003 predicts no loss of function.	pvs1_gene_context pvs1_variant_assessment spliceai pvs1_generic_framework
PS1	N/A	Not applicable: intronic variant has no amino-acid change (p.?) to compare with an established pathogenic variant.
PS2	Not assessed	Not assessed: no case-level de novo evidence (parental genotypes or phenotype-consistent proband) was available.
PS3	Not assessed	Not assessed: no functional assay data (splicing or enzymatic studies) for this variant was available; only in silico prediction exists.
PS4	Not assessed	Not assessed: no case-series or case-control enrichment data for this exact variant was available.
PM1	N/A	Not applicable: deep intronic variant with no protein-coding consequence, so there is no residue or domain to evaluate.
PM2	Not met	Not met: variant is present in population databases (5/1,613,834 alleles in gnomAD v4.1).	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	Not assessed	Not assessed: no second pathogenic variant, parental testing, or phase information documented.
PM4	N/A	Not applicable: no protein-length change (p.?), and SpliceAI max delta 0.003 predicts no in-frame exon skip.	pvs1_variant_assessment spliceai
PM5	N/A	Not applicable: intronic variant produces no amino-acid substitution, so no residue to compare with pathogenic missense variants.	pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence or parental genotype information reported.
PP1	Not assessed	Not assessed: no segregation data from affected or unaffected relatives was reported.
PP2	N/A	Not applicable: variant is intronic with no amino-acid substitution, so missense-based constraint logic does not apply.
PP3	Not met	Not met: SpliceAI max delta 0.003, far below the 0.2 threshold for PP3.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient phenotype or highly specific clinical findings were provided.
PP5	Not met	Not met: ClinVar record has only a single-submitter uncertain-significance assertion, with no expert-panel submission.	clinvar
BA1	Not met	Not met: allele frequency 3.1e-06 (5/1,613,834) in gnomAD v4.1, far below the >5% stand-alone benign threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not assessed	Not assessed: no disease-specific expected allele-frequency threshold or penetrance estimate available for comparison.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: no phenotyped healthy adult carriers documented; absence of homozygotes alone is insufficient.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no functional study showing normal function for this variant was available.
BS4	Not assessed	Not assessed: no tested relatives reported, so no non-segregation observation is available.
BP1	N/A	Not applicable: variant is intronic, not missense, so missense-specific BP1 logic does not apply.
BP2	Not assessed	Not assessed: no phase information (cis/trans) relative to a pathogenic variant was available.
BP3	N/A	Not applicable: single-nucleotide intronic substitution, not an in-frame indel in a repetitive region.	pvs1_variant_assessment
BP4	Met	Met (supporting): SpliceAI max delta 0.003, well below the 0.1 threshold for BP4.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no evidence that the phenotype is better explained by an alternate molecular cause.
BP6	Not met	Not met: no expert-panel benign or likely benign classification exists for this variant in ClinVar.	clinvar
BP7	N/A	Not applicable: deep intronic variant, not a synonymous coding change; splice impact is captured by BP4.

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