rs118053940

chr15-90084321-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 14/20 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 5.11

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 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, Uncertain_significance=1, Benign=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. This position pass quality control queck.
• BS2: High AC in GnomAd at 545 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH2	NM_002168.4	c.1304C>T	p.Thr435Met	missense_variant	11/11	ENST00000330062.8
IDH2	NM_001289910.1	c.1148C>T	p.Thr383Met	missense_variant	11/11
IDH2	NM_001290114.2	c.914C>T	p.Thr305Met	missense_variant	9/9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 545 AN: 152160 Hom.: 3 Cov.: 32

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.: 5 AF XY: 0.00368 AC XY: 499 AN XY: 135728

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.: 52 Cov.: 31 AF XY: 0.00637 AC XY: 4634 AN XY: 727174

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.: 3 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74448

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.: 8

Bravo AF: 0.00363

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00374 AC: 454

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

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	Jan 01, 2024	IDH2: BP4, BS2 -

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

- -

IDH2-related condition Benign:1

Likely benign, criteria provided, single submitter

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). -

D-2-hydroxyglutaric aciduria 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Benign	0.38	T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0092	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs118053940; hg19: chr15-90627553; COSMIC: COSV51561910; COSMIC: COSV51561910;