rs142816010

Variant names:

• chr15-90088364-C-T
• rs142816010
• NM_002168.4:c.673G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002168.4(IDH2):​c.673G>A​(p.Asp225Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,613,648 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D225E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 7.55
• Publications: 9 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 -9 ACMG points.

• BP6: Variant 15-90088364-C-T is Benign according to our data. Variant chr15-90088364-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211176.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000322 (471/1461304) while in subpopulation MID AF = 0.000559 (3/5364). AF 95% confidence interval is 0.000323. There are 1 homozygotes in GnomAdExome4. There are 228 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 52 AD gene.

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.673G>A	p.Asp225Asn	missense	Exon 5 of 11	NP_002159.2
	IDH2	NM_001289910.1		c.517G>A	p.Asp173Asn	missense	Exon 5 of 11	NP_001276839.1	P48735-2
	IDH2	NM_001290114.2		c.283G>A	p.Asp95Asn	missense	Exon 3 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.673G>A	p.Asp225Asn	missense	Exon 5 of 11	ENSP00000331897.4	P48735-1
	IDH2	ENST00000864224.1		c.757G>A	p.Asp253Asn	missense	Exon 6 of 12	ENSP00000534283.1
	IDH2	ENST00000864227.1		c.742G>A	p.Asp248Asn	missense	Exon 6 of 12	ENSP00000534286.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152226 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000291 AC: 73 AN: 250944 AF XY: 0.000317

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000322 AC: 471 AN: 1461304 Hom.: 1 Cov.: 33 AF XY: 0.000314 AC XY: 228 AN XY: 726976

African (AFR) AF: 0.0000897 AC: 3 AN: 33462

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86230

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53338

Middle Eastern (MID) AF: 0.000559 AC: 3 AN: 5364

European-Non Finnish (NFE) AF: 0.000353 AC: 392 AN: 1112010

Other (OTH) AF: 0.000215 AC: 13 AN: 60340

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152344 Hom.: 0 Cov.: 31 AF XY: 0.000282 AC XY: 21 AN XY: 74498

African (AFR) AF: 0.000240 AC: 10 AN: 41590

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.87
MVP		0.85
MPC		1.4
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.63
gMVP		0.91
Mutation Taster		=49/51	disease causing

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: rs142816010; hg19: chr15-90631596; COSMIC: COSV106096283;