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IDH2c.430G>CUncertain significance
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Variant interpretation report

IDH2 c.430G>C, p.(Gly144Arg)

NM_002168.2:c.430G>C NP_002159.2:p.(Gly144Arg) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About IDH2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: IDH2, a cell metabolism enzyme, is recurrently mutated in various cancer types including acute myeloid leukemia, glioblastoma, and cholangiocarcinoma.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 2 not met · 21 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 1

PM2 ModerateThis 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. Details ▾Hide ▴
Rule
PM2 is met when population frequency is below the rarity threshold for the disorder context.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 2 · evaluated, threshold not reached

BA1 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 21 · no assessment recorded

PS1 No pathogenic variant causing the same amino acid change was identified in the available germline database evidence, so PS1 was not assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result for NM_002168.2:c.430G>C.
Still missing
  • No ClinVar entry was identified for this variant.
  • No codon-level pathogenic comparison source was available.
Sources
clinvar ↗
PS2 No de novo data with confirmed maternity and paternity were identified, so PS2 was not assessed. Details ▾Hide ▴
Still missing
  • No family-based de novo data were available.
PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed. Details ▾Hide ▴
Evidence considered
  • OncoKB has not reviewed this specific variant.
Still missing
  • No variant-specific functional assay data were available.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • The variant was not reported in ClinVar and was absent from gnomAD.
Still missing
  • No germline case series or case-control data were available.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review did not show a visible residue row for G144 and was labeled uncertain.
Still missing
  • Cancer Hotspots review was marked uncertain and needs human review.
Sources
hotspots ↗
PM3 No data were identified showing this variant in trans with a pathogenic variant for a recessive disorder, so PM3 was not assessed. Details ▾Hide ▴
Still missing
  • No phase or recessive case data were available.
PM5 No pathogenic missense comparison at the same codon was identified from the available evidence, so PM5 was not assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result for this variant.
Still missing
  • No codon-level pathogenic comparison source was available.
Sources
clinvar ↗
PM6 No assumed de novo occurrence without confirmed parental relationships was identified, so PM6 was not assessed. Details ▾Hide ▴
Still missing
  • No de novo case data were available.
PP1 No segregation data were identified, so PP1 was not assessed. Details ▾Hide ▴
Still missing
  • No family segregation information was available.
PP2 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. Details ▾Hide ▴
Evidence considered
  • No gene-specific VCEP or local gene framework was available.
Still missing
  • No gene-specific missense constraint or mechanism framework was available.
Sources
final_classification_framework
PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01.
Still missing
  • No registered missense-prediction source was available in the citation set.
Sources
spliceai ↗
PP4 No phenotype data were provided to determine whether the clinical presentation is highly specific for an IDH2-related disorder, so PP4 was not assessed. Details ▾Hide ▴
Still missing
  • No phenotype or diagnostic specificity information was available.
PP5 No reputable external source classification for this specific variant was identified, so PP5 was not assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result.
  • OncoKB has not reviewed this specific variant.
Still missing
  • No ClinVar submission or other registered pathogenic assertion was available.
Sources
clinvar ↗oncokb ↗
BS2 No data were identified showing this variant in healthy adult individuals for a fully penetrant dominant condition, so BS2 was not assessed. Details ▾Hide ▴
Still missing
  • No healthy adult observation data were available.
BS3 No well-established functional studies demonstrating a normal or benign effect of this specific variant were identified, so BS3 was not assessed. Details ▾Hide ▴
Evidence considered
  • OncoKB has not reviewed this specific variant.
Still missing
  • No benign functional assay data were available.
Sources
oncokb ↗
BS4 No segregation data showing lack of co-segregation with disease were identified, so BS4 was not assessed. Details ▾Hide ▴
Still missing
  • No family segregation information was available.
BP1 Available evidence did not establish that IDH2 disease is primarily caused by truncating variants rather than missense variants, so BP1 was not assessed. Details ▾Hide ▴
Evidence considered
  • No gene-specific VCEP or local gene framework was available.
Still missing
  • No gene-specific mechanism framework supporting BP1 was available.
Sources
final_classification_framework
BP2 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. Details ▾Hide ▴
Still missing
  • No phase data were available.
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01.
Still missing
  • No registered missense-prediction source supporting a benign effect was available.
Sources
spliceai ↗
BP5 No alternate molecular explanation for the phenotype was provided, so BP5 was not assessed. Details ▾Hide ▴
Still missing
  • No phenotype-level alternate diagnosis data were available.
BP6 No reputable external source classified this specific variant as benign or likely benign, so BP6 was not assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result.
  • OncoKB has not reviewed this specific variant.
Still missing
  • No ClinVar submission or other registered benign assertion was available.
Sources
clinvar ↗oncokb ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AAlthough 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. Details ▾Hide ▴
Rule
Generic PVS1 fallback applies only to qualifying null variants after gene-level eligibility is established.
Evidence considered
  • IDH2 loss of function was considered eligible for generic PVS1 review at the gene level.
  • NM_002168.2:c.430G>C is classified in the generic PVS1 scaffold as variant_bucket 'other' with apply_generic_pvs1_framework false.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/AThis variant is a missense substitution and does not change protein length, so PM4 does not apply. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Gly144Arg) / p.(G144R).
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region, so BP3 does not apply. Details ▾Hide ▴
Evidence considered
  • Protein consequence is a missense substitution.
BP7 N/AThis variant is not synonymous and is not a deep intronic change, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Gly144Arg) / p.(G144R).

Identifiers

Gene
IDH2
Transcript
NM_002168.2
Coding (HGVS c.)
NM_002168.2:c.430G>C
Protein (HGVS p.)
NP_002159.2:p.(Gly144Arg)
GRCh38
chr15:90088691 C>G
GRCh37
chr15:90631923 C>G

Gene diagram

Every interpreted variant in IDH2, mapped onto the exon structure of NM_002168.2. Select a row to find it on the plot.

IDH2NM_002168.2
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01.
Still missing
  • No registered missense-prediction source was available in the citation set.
Sources
spliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01.
Still missing
  • No registered missense-prediction source supporting a benign effect was available.
Sources
spliceai ↗
BP7 N/AThis variant is not synonymous and is not a deep intronic change, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Gly144Arg) / p.(G144R).

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: IDH2, a cell metabolism enzyme, is recurrently mutated in various cancer types including acute myeloid leukemia, glioblastoma, and cholangiocarcinoma.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.