15-90084384-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002168.4(IDH2):c.1272-31A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,597,912 control chromosomes in the GnomAD database, including 56,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (12595 hom., cov: 32)
  • Exomes 𝑓: 0.23 (43660 hom.)
• Consequence: IDH2 NM_002168.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.904

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-90084384-T-C is Benign according to our data. Variant chr15-90084384-T-C is described in ClinVar as [Benign]. Clinvar id is 1260667.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH2	NM_002168.4	c.1272-31A>G		intron_variant		ENST00000330062.8
IDH2	NM_001289910.1	c.1116-31A>G		intron_variant
IDH2	NM_001290114.2	c.882-31A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH2	ENST00000330062.8	c.1272-31A>G		intron_variant		1	NM_002168.4	P1
IDH2	ENST00000540499.2	c.1116-31A>G		intron_variant		2
IDH2	ENST00000559482.5	c.852-31A>G		intron_variant		5
IDH2	ENST00000560061.1	c.*897-31A>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53777 AN: 151952 Hom.: 12548 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.322

GnomAD3 exomes AF: 0.259 AC: 61017 AN: 235948 Hom.: 9383 AF XY: 0.250 AC XY: 31879 AN XY: 127632

Gnomad AFR exome AF: 0.694

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.226

Gnomad SAS exome AF: 0.241

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.234 AC: 337845 AN: 1445842 Hom.: 43660 Cov.: 27 AF XY: 0.233 AC XY: 167297 AN XY: 719312

Gnomad4 AFR exome AF: 0.701

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.187

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.218

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.354 AC: 53876 AN: 152070 Hom.: 12595 Cov.: 32 AF XY: 0.349 AC XY: 25965 AN XY: 74322

Gnomad4 AFR AF: 0.679

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.221

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.318

Alfa AF: 0.264 Hom.: 1397

Bravo AF: 0.374

Asia WGS AF: 0.230 AC: 801 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.6
Dann	Benign	0.79

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: rs60147683; hg19: chr15-90627616; COSMIC: COSV51561471; COSMIC: COSV51561471;