rs118101777

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_002168.4(IDH2):c.782G>A(p.Arg261His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,614,202 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 4 hom. )

Consequence

IDH2
NM_002168.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.84

Publications

22 publications found

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 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

IDH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 11: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.059553802).

BP6

Variant 15-90087472-C-T is Benign according to our data. Variant chr15-90087472-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00158 (241/152348) while in subpopulation NFE AF = 0.00231 (157/68030). AF 95% confidence interval is 0.00201. There are 2 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 241 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH2	NM_002168.4 link	c.782G>A	p.Arg261His	missense_variant	Exon 6 of 11	ENST00000330062.8	NP_002159.2	P48735-1
IDH2	NM_001289910.1 link	c.626G>A	p.Arg209His	missense_variant	Exon 6 of 11		NP_001276839.1	P48735-2
IDH2	NM_001290114.2 link	c.392G>A	p.Arg131His	missense_variant	Exon 4 of 9		NP_001277043.1	P48735B4DSZ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8 link	c.782G>A	p.Arg261His	missense_variant	Exon 6 of 11	1	NM_002168.4	ENSP00000331897.4		P48735-1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

241

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00198

AC:

499

AN:

251486

AF XY:

0.00210

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00670

Gnomad NFE exome

AF:

0.00280

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00202

AC:

2946

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

1461

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00635

AC:

339

AN:

53418

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00224

AC:

2495

AN:

1111988

Other (OTH)

AF:

0.00124

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

175

351

526

702

877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00158

AC:

241

AN:

152348

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

41584

American (AMR)

AF:

0.000261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00640

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00231

AC:

157

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.00130

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00199

AC:

242

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00224

EpiControl

AF:

0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

D-2-hydroxyglutaric aciduria 2

Benign:2

Jan 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 17, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IDH2: PP3, BS2 -

IDH2-related disorder

Benign:1

Feb 04, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;D;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.5

H;.;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.92

MVP

0.94

MPC

1.6

ClinPred

0.11

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.92

Mutation Taster

=66/34

polymorphism

(source)

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

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rs118101777

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over