chr15-90084321-G-A
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_002168.4(IDH2):c.1304C>T(p.Thr435Met) variant causes a missense change. The variant allele was found at a frequency of 0.00627 in 1,614,042 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0066 ( 52 hom. )
Consequence
IDH2
NM_002168.4 missense
NM_002168.4 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 5.11
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 -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.009162426).
BP6
Variant 15-90084321-G-A is Benign according to our data. Variant chr15-90084321-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158664.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr15-90084321-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00358 (545/152278) while in subpopulation NFE AF= 0.00676 (460/68024). AF 95% confidence interval is 0.00625. There are 3 homozygotes in gnomad4. There are 237 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 545 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDH2 | NM_002168.4 | c.1304C>T | p.Thr435Met | missense_variant | 11/11 | ENST00000330062.8 | |
IDH2 | NM_001289910.1 | c.1148C>T | p.Thr383Met | missense_variant | 11/11 | ||
IDH2 | NM_001290114.2 | c.914C>T | p.Thr305Met | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDH2 | ENST00000330062.8 | c.1304C>T | p.Thr435Met | missense_variant | 11/11 | 1 | NM_002168.4 | P1 | |
IDH2 | ENST00000540499.2 | c.1148C>T | p.Thr383Met | missense_variant | 11/11 | 2 | |||
IDH2 | ENST00000559482.5 | c.884C>T | p.Thr295Met | missense_variant | 8/8 | 5 | |||
IDH2 | ENST00000560061.1 | c.*929C>T | 3_prime_UTR_variant, NMD_transcript_variant | 9/9 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00358 AC: 545AN: 152160Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00362 AC: 910AN: 251056Hom.: 5 AF XY: 0.00368 AC XY: 499AN XY: 135728
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GnomAD4 exome AF: 0.00655 AC: 9579AN: 1461764Hom.: 52 Cov.: 31 AF XY: 0.00637 AC XY: 4634AN XY: 727174
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GnomAD4 genome AF: 0.00358 AC: 545AN: 152278Hom.: 3 Cov.: 32 AF XY: 0.00318 AC XY: 237AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | IDH2: BP4, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 26, 2016 | - - |
Enchondromatosis Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 18, 2014 | - - |
D-2-hydroxyglutaric aciduria 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
IDH2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 29, 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
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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