15-90084832-T-C

Position:

• chr15-90084832-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS2_Supporting

The NM_002168.4(IDH2):​c.1255A>G​(p.Ile419Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,670 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32506853).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH2	NM_002168.4	c.1255A>G	p.Ile419Val	missense_variant	10/11	ENST00000330062.8
IDH2	NM_001289910.1	c.1099A>G	p.Ile367Val	missense_variant	10/11
IDH2	NM_001290114.2	c.865A>G	p.Ile289Val	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH2	ENST00000330062.8	c.1255A>G	p.Ile419Val	missense_variant	10/11	1	NM_002168.4	P1
IDH2	ENST00000540499.2	c.1099A>G	p.Ile367Val	missense_variant	10/11	2
IDH2	ENST00000559482.5	c.851+169A>G		intron_variant		5
IDH2	ENST00000560061.1	c.*880A>G		3_prime_UTR_variant, NMD_transcript_variant	8/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251370 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461670 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

D-2-hydroxyglutaric aciduria 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 29, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 419 of the IDH2 protein (p.Ile419Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with IDH2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.035
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.53	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.29	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.011	B;.
Vest4		0.61
MutPred		0.41		Loss of catalytic residue at I419 (P = 0.1607);.;
MVP		0.73
MPC		0.43
ClinPred		0.37	T
GERP RS		5.6
Varity_R		0.26
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1423721679; hg19: chr15-90628064;