15-90085362-C-T

Position:

• chr15-90085362-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002168.4(IDH2):​c.993G>A​(p.Thr331=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,557,318 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: IDH2 NM_002168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.260

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=-0.67).
• BP6: Variant 15-90085362-C-T is Benign according to our data. Variant chr15-90085362-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1830/152264) while in subpopulation AFR AF= 0.042 (1747/41550). AF 95% confidence interval is 0.0404. There are 32 homozygotes in gnomad4. There are 842 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1830 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH2	NM_002168.4	c.993G>A	p.Thr331=	synonymous_variant	8/11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.837G>A	p.Thr279=	synonymous_variant	8/11		NP_001276839.1
IDH2	NM_001290114.2	c.603G>A	p.Thr201=	synonymous_variant	6/9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.993G>A	p.Thr331=	synonymous_variant	8/11	1	NM_002168.4	ENSP00000331897	P1
IDH2	ENST00000540499.2	c.837G>A	p.Thr279=	synonymous_variant	8/11	2		ENSP00000446147
IDH2	ENST00000559482.5	c.666G>A	p.Thr222=	synonymous_variant	6/8	5		ENSP00000453016
IDH2	ENST00000560061.1	c.*618G>A		3_prime_UTR_variant, NMD_transcript_variant	6/9	2		ENSP00000453254

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1814 AN: 152146 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00282 AC: 463 AN: 164296 Hom.: 10 AF XY: 0.00206 AC XY: 179 AN XY: 86760

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.00187

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000807

Gnomad SAS exome AF: 0.000258

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000439

GnomAD4 exome AF: 0.00121 AC: 1707 AN: 1405054 Hom.: 37 Cov.: 32 AF XY: 0.00103 AC XY: 713 AN XY: 693638

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000453

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.0120 AC: 1830 AN: 152264 Hom.: 32 Cov.: 32 AF XY: 0.0113 AC XY: 842 AN XY: 74444

Gnomad4 AFR AF: 0.0420

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00526 Hom.: 8

Bravo AF: 0.0138

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	See Variant Classification Assertion Criteria. -

D-2-hydroxyglutaric aciduria 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 19, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.93
DANN	Benign	0.75
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: rs61737002; hg19: chr15-90628594;