chr15-90084821-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7
The NM_002168.4(IDH2):c.1266C>T(p.Leu422=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
IDH2
NM_002168.4 synonymous
NM_002168.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.333
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 Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP7
Synonymous conserved (PhyloP=-0.333 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDH2 | NM_002168.4 | c.1266C>T | p.Leu422= | synonymous_variant | 10/11 | ENST00000330062.8 | |
IDH2 | NM_001289910.1 | c.1110C>T | p.Leu370= | synonymous_variant | 10/11 | ||
IDH2 | NM_001290114.2 | c.876C>T | p.Leu292= | synonymous_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDH2 | ENST00000330062.8 | c.1266C>T | p.Leu422= | synonymous_variant | 10/11 | 1 | NM_002168.4 | P1 | |
IDH2 | ENST00000540499.2 | c.1110C>T | p.Leu370= | synonymous_variant | 10/11 | 2 | |||
IDH2 | ENST00000559482.5 | c.851+180C>T | intron_variant | 5 | |||||
IDH2 | ENST00000560061.1 | c.*891C>T | 3_prime_UTR_variant, NMD_transcript_variant | 8/9 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461198Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726934
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74462
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
D-2-hydroxyglutaric aciduria 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 10, 2022 | This variant has not been reported in the literature in individuals affected with IDH2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is present in population databases (rs202133711, gnomAD 0.01%). This sequence change affects codon 422 of the IDH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the IDH2 protein. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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