rs118053940

Positions:

chr15-90084321-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002168.4(IDH2):c.1304C>T(p.Thr435Met) variant causes a missense change. The variant allele was found at a frequency of 0.00627 in 1,614,042 control chromosomes in the GnomAD database, including 55 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0066 ( 52 hom. )

Consequence

IDH2
NM_002168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 5.11

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009162426).

BP6

Variant 15-90084321-G-A is Benign according to our data. Variant chr15-90084321-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158664.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr15-90084321-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00358 (545/152278) while in subpopulation NFE AF= 0.00676 (460/68024). AF 95% confidence interval is 0.00625. There are 3 homozygotes in gnomad4. There are 237 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 545 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IDH2	NM_002168.4 linkuse as main transcript	c.1304C>T	p.Thr435Met	missense_variant	11/11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1 linkuse as main transcript	c.1148C>T	p.Thr383Met	missense_variant	11/11		NP_001276839.1
IDH2	NM_001290114.2 linkuse as main transcript	c.914C>T	p.Thr305Met	missense_variant	9/9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8 linkuse as main transcript	c.1304C>T	p.Thr435Met	missense_variant	11/11	1	NM_002168.4	ENSP00000331897	P1	P48735-1
IDH2	ENST00000540499.2 linkuse as main transcript	c.1148C>T	p.Thr383Met	missense_variant	11/11	2		ENSP00000446147		P48735-2
IDH2	ENST00000559482.5 linkuse as main transcript	c.884C>T	p.Thr295Met	missense_variant	8/8	5		ENSP00000453016
IDH2	ENST00000560061.1 linkuse as main transcript	c.*929C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9	2		ENSP00000453254

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

545

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00676

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00362

AC:

910

AN:

251056

Hom.:

AF XY:

0.00368

AC XY:

499

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000948

Gnomad FIN exome

AF:

0.00228

Gnomad NFE exome

AF:

0.00646

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00655

AC:

9579

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00637

AC XY:

4634

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00109

Gnomad4 FIN exome

AF:

0.00249

Gnomad4 NFE exome

AF:

0.00794

Gnomad4 OTH exome

AF:

0.00649

GnomAD4 genome

AF:

0.00358

AC:

545

AN:

152278

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

237

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00676

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00575

Hom.:

Bravo

AF:

0.00363

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00374

AC:

454

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	IDH2: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Enchondromatosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 18, 2014

- -

D-2-hydroxyglutaric aciduria 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

IDH2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2020

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

0.096

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.38

T;T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.0092

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

N;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

0.29

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.027

B;.;.

Vest4

0.27

MVP

0.74

MPC

0.65

ClinPred

0.012

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.72

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