15-90084337-G-A

Position:

• chr15-90084337-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_002168.4(IDH2):​c.1288C>T​(p.His430Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.24

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-90084337-G-A is Pathogenic according to our data. Variant chr15-90084337-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427064.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH2	NM_002168.4	c.1288C>T	p.His430Tyr	missense_variant	11/11	ENST00000330062.8
IDH2	NM_001289910.1	c.1132C>T	p.His378Tyr	missense_variant	11/11
IDH2	NM_001290114.2	c.898C>T	p.His300Tyr	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH2	ENST00000330062.8	c.1288C>T	p.His430Tyr	missense_variant	11/11	1	NM_002168.4	P1
IDH2	ENST00000540499.2	c.1132C>T	p.His378Tyr	missense_variant	11/11	2
IDH2	ENST00000559482.5	c.868C>T	p.His290Tyr	missense_variant	8/8	5
IDH2	ENST00000560061.1	c.*913C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2015

The H430Y variant in the IDH2 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The H430Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H430Y variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The H430Y variant is a strong candidate for a disease-causing varian, however, the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Uncertain	0.53	D;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.077	T;T;T
Polyphen		0.94	P;.;.
Vest4		0.87
MutPred		0.25		Gain of ubiquitination at K426 (P = 0.0707);.;.;
MVP		0.80
MPC		1.3
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.37
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307936; hg19: chr15-90627569;