NM_002168.4:c.996C>T

Variant names:

• chr15-90085359-G-A
• rs61737003
• NM_002168.4:c.996C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002168.4(IDH2):​c.996C>T​(p.Ser332Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,557,252 control chromosomes in the GnomAD database, including 1,945 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (915 hom., cov: 32)
  • Exomes 𝑓: 0.020 (1030 hom.)
• Consequence: IDH2 NM_002168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.13
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-90085359-G-A is Benign according to our data. Variant chr15-90085359-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 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.996C>T	p.Ser332Ser	synonymous	Exon 8 of 11	NP_002159.2
	IDH2	NM_001289910.1		c.840C>T	p.Ser280Ser	synonymous	Exon 8 of 11	NP_001276839.1	P48735-2
	IDH2	NM_001290114.2		c.606C>T	p.Ser202Ser	synonymous	Exon 6 of 9	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.996C>T	p.Ser332Ser	synonymous	Exon 8 of 11	ENSP00000331897.4	P48735-1
	IDH2	ENST00000864224.1		c.1080C>T	p.Ser360Ser	synonymous	Exon 9 of 12	ENSP00000534283.1
	IDH2	ENST00000864227.1		c.1065C>T	p.Ser355Ser	synonymous	Exon 9 of 12	ENSP00000534286.1

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10918 AN: 152066 Hom.: 906 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0282 AC: 4639 AN: 164566 AF XY: 0.0242

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.0000806

Gnomad FIN exome AF: 0.0263

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0244

GnomAD4 exome AF: 0.0201 AC: 28254 AN: 1405068 Hom.: 1030 Cov.: 32 AF XY: 0.0194 AC XY: 13434 AN XY: 693674

African (AFR) AF: 0.215 AC: 6887 AN: 32046

American (AMR) AF: 0.0257 AC: 927 AN: 36088

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 379 AN: 25206

East Asian (EAS) AF: 0.000136 AC: 5 AN: 36676

South Asian (SAS) AF: 0.0155 AC: 1238 AN: 79728

European-Finnish (FIN) AF: 0.0245 AC: 1213 AN: 49544

Middle Eastern (MID) AF: 0.0389 AC: 222 AN: 5700

European-Non Finnish (NFE) AF: 0.0144 AC: 15613 AN: 1081828

Other (OTH) AF: 0.0304 AC: 1770 AN: 58252

GnomAD4 genome AF: 0.0720 AC: 10951 AN: 152184 Hom.: 915 Cov.: 32 AF XY: 0.0701 AC XY: 5217 AN XY: 74394

African (AFR) AF: 0.207 AC: 8574 AN: 41502

American (AMR) AF: 0.0403 AC: 616 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4826

European-Finnish (FIN) AF: 0.0268 AC: 284 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0174 AC: 1183 AN: 67994

Other (OTH) AF: 0.0620 AC: 131 AN: 2112

Alfa AF: 0.0279 Hom.: 378

Bravo AF: 0.0798

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	D-2-hydroxyglutaric aciduria 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.035
DANN	Benign	0.57
PhyloP100		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61737003; hg19: chr15-90628591; COSMIC: COSV51561820; COSMIC: COSV51561820;