rs536071174

Variant names:

• chr15-90090492-C-A
• rs536071174
• NM_002168.4:c.360G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-90090492-C-A
• chr15-90090492-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002168.4(IDH2):​c.360G>T​(p.Glu120Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E120E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0730
• Publications: 0 publications found

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]

IDH2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• d-2-hydroxyglutaric aciduria 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• D-2-hydroxyglutaric aciduria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH2	NM_002168.4	c.360G>T	p.Glu120Asp	missense_variant	Exon 3 of 11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.204G>T	p.Glu68Asp	missense_variant	Exon 3 of 11		NP_001276839.1
IDH2	NM_001290114.2	c.-17-1745G>T		intron_variant	Intron 1 of 8		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.360G>T	p.Glu120Asp	missense_variant	Exon 3 of 11	1	NM_002168.4	ENSP00000331897.4
IDH2	ENST00000540499.2	c.204G>T	p.Glu68Asp	missense_variant	Exon 3 of 11	2		ENSP00000446147.2
IDH2	ENST00000559482.5	c.207+1061G>T		intron_variant	Intron 2 of 7	5		ENSP00000453016.1
IDH2	ENST00000560061.1	n.116-1745G>T		intron_variant	Intron 1 of 8	2		ENSP00000453254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.22
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.5	M;.
PhyloP100		0.073
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.8	D;D
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.032	D;D
Vest4		0.60
ClinPred		0.93	D
GERP RS		1.0
Varity_R		0.89
gMVP		0.90
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs536071174; hg19: chr15-90633724;