NM_002168.2:c.430G>C

IDH2 · NP_002159.2:p.(Gly144Arg) · NM_002168.2

GRCh37: chr15:90631923 C>G · GRCh38: chr15:90088691 C>G

Gene: IDH2 Transcript: NM_002168.2

Final call

VUS

PM2_Moderate

Variant details

Gene

IDH2

Transcript

NM_002168.2

Protein

NP_002159.2:p.(Gly144Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The IDH2 c.430G>C (p.Gly144Arg; p.G144R) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting PM2 because the observed allele frequency of 0 is below the 0.1% threshold.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which argues against a splicing mechanism but does not establish the effect of the missense substitution itself.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Although IDH2 is eligible for generic PVS1 consideration at the gene level, this variant is a missense substitution and does not create a nonsense, frameshift, or canonical +/-1,2 splice-site change, so PVS1 does not apply.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No pathogenic variant causing the same amino acid change was identified in the available germline database evidence, so PS1 was not assessed.	clinvar
PS2	Not assessed	No de novo data with confirmed maternity and paternity were identified, so PS2 was not assessed.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed.	oncokb
PS4	Not assessed	No case-control or enrichment data were identified showing this variant is more prevalent in affected individuals than in controls, so PS4 was not assessed.	clinvar gnomad_v2 gnomad_v4
PM1	Not assessed	Available hotspot review did not confirm that this variant lies in a well-established mutational hotspot or critical functional domain without benign variation, so PM1 was not assessed.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed allele frequency 0), which is below the default PM2 rarity threshold of 0.1% for a rare germline variant.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant for a recessive disorder, so PM3 was not assessed.
PM4	N/A	This variant is a missense substitution and does not change protein length, so PM4 does not apply.
PM5	Not assessed	No pathogenic missense comparison at the same codon was identified from the available evidence, so PM5 was not assessed.	clinvar
PM6	Not assessed	No assumed de novo occurrence without confirmed parental relationships was identified, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified, so PP1 was not assessed.
PP2	Not assessed	Available evidence did not establish that missense variation is a common disease mechanism for IDH2 with a low rate of benign missense variation, so PP2 was not assessed.	final_classification_framework
PP3	Not assessed	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), but the available registered sources do not provide sufficient missense-prediction evidence to support a damaging computational conclusion, so PP3 was not assessed.	spliceai
PP4	Not assessed	No phenotype data were provided to determine whether the clinical presentation is highly specific for an IDH2-related disorder, so PP4 was not assessed.
PP5	Not assessed	No reputable external source classification for this specific variant was identified, so PP5 was not assessed.	clinvar oncokb
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed allele frequency 0), which is below the BA1 benign threshold of 1.0%; therefore BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed allele frequency 0), which is below the BS1 benign threshold of 0.3%; therefore BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data were identified showing this variant in healthy adult individuals for a fully penetrant dominant condition, so BS2 was not assessed.
BS3	Not assessed	No well-established functional studies demonstrating a normal or benign effect of this specific variant were identified, so BS3 was not assessed.	oncokb
BS4	Not assessed	No segregation data showing lack of co-segregation with disease were identified, so BS4 was not assessed.
BP1	Not assessed	Available evidence did not establish that IDH2 disease is primarily caused by truncating variants rather than missense variants, so BP1 was not assessed.	final_classification_framework
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis for any inheritance pattern, so BP2 was not assessed.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region, so BP3 does not apply.
BP4	Not assessed	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), but this alone does not support a benign computational conclusion for the amino acid substitution, so BP4 was not assessed.	spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided, so BP5 was not assessed.
BP6	Not assessed	No reputable external source classified this specific variant as benign or likely benign, so BP6 was not assessed.	clinvar oncokb
BP7	N/A	This variant is not synonymous and is not a deep intronic change, so BP7 does not apply.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.