IDH2

isocitrate dehydrogenase (NADP(+)) 2, the group of Isocitrate dehydrogenases

Basic information

Region (hg38): 15:90083044-90102477

Links

ENSG00000182054 ∙ NCBI:3418 ∙ OMIM:147650 ∙ HGNC:5383 ∙ Uniprot:P48735 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• d-2-hydroxyglutaric aciduria 2 (Strong), mode of inheritance: AD
• D-2-hydroxyglutaric aciduria (Supportive), mode of inheritance: AD
• mitochondrial disease (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
D-2-hydroxyglutaric aciduria 2	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Biochemical; Cardiovascular; Craniofacial; Neurologic	20847235

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IDH2 gene.

• D-2-hydroxyglutaric aciduria 2 (141 variants)
• not provided (58 variants)
• not specified (22 variants)
• Inborn genetic diseases (9 variants)
• Squamous cell carcinoma of the head and neck (2 variants)
• Multiple myeloma (2 variants)
• Enchondromatosis (2 variants)
• Neoplasm of the large intestine (2 variants)
• Acute myeloid leukemia (2 variants)
• Myelodysplastic syndrome (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IDH2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	40	9	52
missense		2	72	4		78
nonsense			1			1
start loss						0
frameshift			2			2
inframe indel						0
splice donor/acceptor (+/-2bp)			2			2
splice region			5	5	1	11
non coding			2	16	22	40
Total	0	2	82	60	31

Variants in IDH2

This is a list of pathogenic ClinVar variants found in the IDH2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-90084256-G-A		not specified	Uncertain significance (May 19, 2016)
15-90084266-C-T		D-2-hydroxyglutaric aciduria 2	Likely benign (Nov 10, 2023)
15-90084267-T-C		D-2-hydroxyglutaric aciduria 2	Uncertain significance (Nov 13, 2023)
15-90084269-C-T		D-2-hydroxyglutaric aciduria 2	Likely benign (Jul 19, 2022)
15-90084271-G-C		D-2-hydroxyglutaric aciduria 2	Uncertain significance (Jun 05, 2019)
15-90084280-G-A		D-2-hydroxyglutaric aciduria 2	Likely benign (Feb 20, 2023)
15-90084300-T-C		D-2-hydroxyglutaric aciduria 2	Uncertain significance (Apr 24, 2023)
15-90084321-G-A		not specified • D-2-hydroxyglutaric aciduria 2 • Enchondromatosis • IDH2-related disorder	Conflicting classifications of pathogenicity (Jan 18, 2024)
15-90084323-G-C		D-2-hydroxyglutaric aciduria 2	Benign (Feb 01, 2024)
15-90084337-G-A			Likely pathogenic (Jul 13, 2015)
15-90084340-C-T		D-2-hydroxyglutaric aciduria 2	Uncertain significance (Jun 09, 2023)
15-90084341-G-A		D-2-hydroxyglutaric aciduria 2	Benign (Jan 30, 2024)
15-90084384-T-C			Benign (May 12, 2021)
15-90084805-A-G		D-2-hydroxyglutaric aciduria 2	Likely benign (Oct 13, 2022)
15-90084806-G-A		D-2-hydroxyglutaric aciduria 2	Likely benign (Jul 10, 2023)
15-90084813-C-T		not specified	Uncertain significance (Dec 14, 2023)
15-90084821-G-A		D-2-hydroxyglutaric aciduria 2	Uncertain significance (Jun 10, 2022)
15-90084826-C-T		Teratoma	Uncertain significance (Jan 01, 2023)
15-90084828-T-A		D-2-hydroxyglutaric aciduria 2	Uncertain significance (Oct 16, 2020)
15-90084832-T-C		D-2-hydroxyglutaric aciduria 2	Uncertain significance (Apr 29, 2022)
15-90084839-C-T		D-2-hydroxyglutaric aciduria 2	Likely benign (Jul 13, 2022)
15-90084859-C-T		Inborn genetic diseases	Uncertain significance (Mar 04, 2024)
15-90084877-C-G		D-2-hydroxyglutaric aciduria 2	Uncertain significance (Nov 27, 2023)
15-90084881-G-A		D-2-hydroxyglutaric aciduria 2	Likely benign (Dec 07, 2023)
15-90084893-C-T		not specified • D-2-hydroxyglutaric aciduria 2	Conflicting classifications of pathogenicity (Jan 29, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IDH2	protein_coding	protein_coding	ENST00000330062	11	19460

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.883	0.117	125738	0	10	125748	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.34	191	251	0.762	0.0000163	2965
Missense in Polyphen		82	137.29	0.59729		1522
Synonymous	-2.17	131	103	1.27	0.00000748	868
Loss of Function	3.54	3	20.2	0.149	8.95e-7	261

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.0000528	0.0000527
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.
• Disease: DISEASE: D-2-hydroxyglutaric aciduria 2 (D2HGA2) [MIM:613657]: A neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine. {ECO:0000269|PubMed:20847235}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:19228619, ECO:0000269|PubMed:25495392}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Note=enetic variations are associated with cartilaginous tumors such as enchondroma or chondrosarcoma. {ECO:0000269|PubMed:26161668}.
• Pathway: Citrate cycle (TCA cycle) - Homo sapiens (human);Glutathione metabolism - Homo sapiens (human);Peroxisome - Homo sapiens (human);The oncogenic action of Succinate;The oncogenic action of Fumarate;Glutaminolysis and Cancer;The oncogenic action of 2-hydroxyglutarate;The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria;The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;fig-met-1-last-solution;TCA Cycle;Citric acid cycle (TCA cycle);Pyruvate metabolism and Citric Acid (TCA) cycle;The citric acid (TCA) cycle and respiratory electron transport;Metabolism;TCA cycle;Transcriptional activation of mitochondrial biogenesis;Mitochondrial biogenesis;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.811

Intolerance Scores

• loftool: 0.307
• rvis_EVS: -0.38
• rvis_percentile_EVS: 27.88

Haploinsufficiency Scores

• pHI: 0.333
• hipred: Y
• hipred_score: 0.685
• ghis: 0.536

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.943

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Idh2
• Phenotype: cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); neoplasm

Gene ontology

• Biological process: carbohydrate metabolic process;glyoxylate cycle;tricarboxylic acid cycle;isocitrate metabolic process;2-oxoglutarate metabolic process;NADP metabolic process;NADP biosynthetic process;negative regulation of glial cell proliferation;negative regulation of glial cell migration;negative regulation of matrix metallopeptidase secretion
• Cellular component: mitochondrion;mitochondrial matrix;peroxisome;cytosol;extracellular exosome
• Molecular function: magnesium ion binding;isocitrate dehydrogenase (NADP+) activity;protein homodimerization activity;NAD binding