rs11540478

Positions:

• chr15-90085305-G-A
• chr15-90085305-G-C
• chr15-90085305-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002168.4(IDH2):​c.1050C>T​(p.Thr350=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,551,798 control chromosomes in the GnomAD database, including 1,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (520 hom., cov: 32)
  • Exomes 𝑓: 0.012 (1080 hom.)
• Consequence: IDH2 NM_002168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.17

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-90085305-G-A is Benign according to our data. Variant chr15-90085305-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90085305-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH2	NM_002168.4	c.1050C>T	p.Thr350=	synonymous_variant	8/11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.894C>T	p.Thr298=	synonymous_variant	8/11		NP_001276839.1
IDH2	NM_001290114.2	c.660C>T	p.Thr220=	synonymous_variant	6/9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.1050C>T	p.Thr350=	synonymous_variant	8/11	1	NM_002168.4	ENSP00000331897	P1
IDH2	ENST00000540499.2	c.894C>T	p.Thr298=	synonymous_variant	8/11	2		ENSP00000446147
IDH2	ENST00000559482.5	c.723C>T	p.Thr241=	synonymous_variant	6/8	5		ENSP00000453016
IDH2	ENST00000560061.1	c.*675C>T		3_prime_UTR_variant, NMD_transcript_variant	6/9	2		ENSP00000453254

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 7880 AN: 151976 Hom.: 519 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0352 AC: 5524 AN: 156770 Hom.: 375 AF XY: 0.0291 AC XY: 2404 AN XY: 82632

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0737

Gnomad ASJ exome AF: 0.000353

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.00257

Gnomad FIN exome AF: 0.000529

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.0242

GnomAD4 exome AF: 0.0116 AC: 16254 AN: 1399704 Hom.: 1080 Cov.: 32 AF XY: 0.0107 AC XY: 7401 AN XY: 690512

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.0718

Gnomad4 ASJ exome AF: 0.000477

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.00347

Gnomad4 FIN exome AF: 0.000571

Gnomad4 NFE exome AF: 0.000896

Gnomad4 OTH exome AF: 0.0254

GnomAD4 genome AF: 0.0519 AC: 7889 AN: 152094 Hom.: 520 Cov.: 32 AF XY: 0.0517 AC XY: 3846 AN XY: 74348

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.0504

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0149 Hom.: 166

Bravo AF: 0.0626

Asia WGS AF: 0.0800 AC: 277 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 27649069) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

D-2-hydroxyglutaric aciduria 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.089
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11540478; hg19: chr15-90628537; COSMIC: COSV51561583; COSMIC: COSV51561583;