rs60147683

Variant names:

• chr15-90084384-T-C
• rs60147683
• NM_002168.4:c.1272-31A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-90084384-T-C
• chr15-90084384-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.904
• Publications: 10 publications found

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]

IDH2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• d-2-hydroxyglutaric aciduria 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• D-2-hydroxyglutaric aciduria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1260667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH2	NM_002168.4	MANE Select	c.1272-31A>G		intron	N/A	NP_002159.2
	IDH2	NM_001289910.1		c.1116-31A>G		intron	N/A	NP_001276839.1	P48735-2
	IDH2	NM_001290114.2		c.882-31A>G		intron	N/A	NP_001277043.1	B4DSZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH2	ENST00000330062.8	TSL:1 MANE Select	c.1272-31A>G		intron	N/A	ENSP00000331897.4	P48735-1
	IDH2	ENST00000864224.1		c.1356-31A>G		intron	N/A	ENSP00000534283.1
	IDH2	ENST00000864227.1		c.1341-31A>G		intron	N/A	ENSP00000534286.1

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

GnomAD2 exomes AF: 0.259 AC: 61017 AN: 235948 AF XY: 0.250

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 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

African (AFR) AF: 0.701 AC: 23191 AN: 33106

American (AMR) AF: 0.266 AC: 11542 AN: 43442

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4845 AN: 25938

East Asian (EAS) AF: 0.213 AC: 8363 AN: 39236

South Asian (SAS) AF: 0.240 AC: 20343 AN: 84832

European-Finnish (FIN) AF: 0.234 AC: 12366 AN: 52776

Middle Eastern (MID) AF: 0.290 AC: 1659 AN: 5718

European-Non Finnish (NFE) AF: 0.218 AC: 239901 AN: 1100974

Other (OTH) AF: 0.261 AC: 15635 AN: 59820

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

African (AFR) AF: 0.679 AC: 28173 AN: 41484

American (AMR) AF: 0.296 AC: 4518 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3470

East Asian (EAS) AF: 0.212 AC: 1090 AN: 5146

South Asian (SAS) AF: 0.221 AC: 1065 AN: 4814

European-Finnish (FIN) AF: 0.234 AC: 2483 AN: 10592

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14953 AN: 67964

Other (OTH) AF: 0.318 AC: 673 AN: 2114

Alfa AF: 0.264 Hom.: 1397

Bravo AF: 0.374

Asia WGS AF: 0.230 AC: 801 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.79
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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