chr15-90084828-T-G

Variant names:

• chr15-90084828-T-G
• NM_002168.4:c.1259A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002168.4(IDH2):​c.1259A>C​(p.His420Pro) variant causes a missense change involving the alteration of a 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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.1259A>C	p.His420Pro	missense_variant	Exon 10 of 11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.1103A>C	p.His368Pro	missense_variant	Exon 10 of 11		NP_001276839.1
IDH2	NM_001290114.2	c.869A>C	p.His290Pro	missense_variant	Exon 8 of 9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.1259A>C	p.His420Pro	missense_variant	Exon 10 of 11	1	NM_002168.4	ENSP00000331897.4

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	0.92
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.99	D;.
Vest4		0.72
MutPred		0.40		Loss of catalytic residue at H420 (P = 0.0123);.;
MVP		0.90
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-90628060;