rs150943639

Positions:

• chr15-90090525-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_002168.4(IDH2):​c.327G>A​(p.Val109=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,614,162 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (13 hom.)
• Consequence: IDH2 NM_002168.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.153

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 15-90090525-C-T is Benign according to our data. Variant chr15-90090525-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158665.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr15-90090525-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00243 (370/152340) while in subpopulation NFE AF= 0.00398 (271/68020). AF 95% confidence interval is 0.00359. There are 0 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 370 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH2	NM_002168.4	c.327G>A	p.Val109=	synonymous_variant	3/11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.171G>A	p.Val57=	synonymous_variant	3/11		NP_001276839.1
IDH2	NM_001290114.2	c.-17-1778G>A		intron_variant			NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.327G>A	p.Val109=	synonymous_variant	3/11	1	NM_002168.4	ENSP00000331897	P1
IDH2	ENST00000540499.2	c.171G>A	p.Val57=	synonymous_variant	3/11	2		ENSP00000446147
IDH2	ENST00000559482.5	c.207+1028G>A		intron_variant		5		ENSP00000453016
IDH2	ENST00000560061.1	c.116-1778G>A		intron_variant, NMD_transcript_variant		2		ENSP00000453254

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00247 AC: 621 AN: 251372 Hom.: 0 AF XY: 0.00243 AC XY: 330 AN XY: 135884

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00388 AC: 5679 AN: 1461822 Hom.: 13 Cov.: 32 AF XY: 0.00362 AC XY: 2633 AN XY: 727202

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00474

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74498

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00304 Hom.: 0

Bravo AF: 0.00247

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 16, 2014

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

IDH2: BP4, BP7 -

D-2-hydroxyglutaric aciduria 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	10
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150943639; hg19: chr15-90633757;