15-90084271-G-C

Position:

chr15-90084271-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_002168.4(IDH2):c.1354C>G(p.Gln452Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q452Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

IDH2
NM_002168.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0780

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051443577).

BS2

High AC in GnomAdExome4 at 7 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
IDH2	NM_002168.4 linkuse as main transcript	c.1354C>G	p.Gln452Glu	missense_variant	11/11	ENST00000330062.8
IDH2	NM_001289910.1 linkuse as main transcript	c.1198C>G	p.Gln400Glu	missense_variant	11/11
IDH2	NM_001290114.2 linkuse as main transcript	c.964C>G	p.Gln322Glu	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH2	ENST00000330062.8 linkuse as main transcript	c.1354C>G	p.Gln452Glu	missense_variant	11/11	1	NM_002168.4	P1	P48735-1
IDH2	ENST00000540499.2 linkuse as main transcript	c.1198C>G	p.Gln400Glu	missense_variant	11/11	2			P48735-2
IDH2	ENST00000559482.5 linkuse as main transcript	c.934C>G	p.Gln312Glu	missense_variant	8/8	5
IDH2	ENST00000560061.1 linkuse as main transcript	c.*979C>G		3_prime_UTR_variant, NMD_transcript_variant	9/9	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250706

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461398

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

D-2-hydroxyglutaric aciduria 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2019

This variant is present in population databases (rs553627406, ExAC 0.05%). This sequence change replaces glutamine with glutamic acid at codon 452 of the IDH2 protein (p.Gln452Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant has not been reported in the literature in individuals 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

0.078

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.051

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

N;.;.

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.33

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0080

D;D;D

Sift4G

Benign

0.67

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.31

MutPred

0.33

Loss of MoRF binding (P = 0.007);.;.;

MVP

0.66

MPC

0.55

ClinPred

0.042

GERP RS

1.8

Varity_R

0.25

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over