rs118101777
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2
The NM_002168.4(IDH2):c.782G>A(p.Arg261His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,614,202 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0020 ( 4 hom. )
Consequence
IDH2
NM_002168.4 missense
NM_002168.4 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 7.84
Genes affected
IDH2 (HGNC:5383): (isocitrate dehydrogenase (NADP(+)) 2) Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
PP3
?
Multiple lines of computational evidence support a deleterious effect 10: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.059553802).
BP6
?
Variant 15-90087472-C-T is Benign according to our data. Variant chr15-90087472-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00158 (241/152348) while in subpopulation NFE AF= 0.00231 (157/68030). AF 95% confidence interval is 0.00201. There are 2 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 241 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDH2 | NM_002168.4 | c.782G>A | p.Arg261His | missense_variant | 6/11 | ENST00000330062.8 | |
IDH2 | NM_001289910.1 | c.626G>A | p.Arg209His | missense_variant | 6/11 | ||
IDH2 | NM_001290114.2 | c.392G>A | p.Arg131His | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDH2 | ENST00000330062.8 | c.782G>A | p.Arg261His | missense_variant | 6/11 | 1 | NM_002168.4 | P1 | |
IDH2 | ENST00000540499.2 | c.626G>A | p.Arg209His | missense_variant | 6/11 | 2 | |||
IDH2 | ENST00000559482.5 | c.455G>A | p.Arg152His | missense_variant | 4/8 | 5 | |||
IDH2 | ENST00000560061.1 | c.*407G>A | 3_prime_UTR_variant, NMD_transcript_variant | 4/9 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00158 AC: 241AN: 152230Hom.: 2 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00198 AC: 499AN: 251486Hom.: 5 AF XY: 0.00210 AC XY: 286AN XY: 135918
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GnomAD4 exome AF: 0.00202 AC: 2946AN: 1461854Hom.: 4 Cov.: 33 AF XY: 0.00201 AC XY: 1461AN XY: 727224
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GnomAD4 genome ? AF: 0.00158 AC: 241AN: 152348Hom.: 2 Cov.: 32 AF XY: 0.00165 AC XY: 123AN XY: 74500
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ESP6500AA
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ExAC
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
D-2-hydroxyglutaric aciduria 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 28, 2022 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 17, 2014 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | IDH2: PP3, BS2 - |
IDH2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 04, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at