rs767090389

Variant names:

• chr15-90084877-C-G
• rs767090389
• NM_002168.4:c.1210G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002168.4(IDH2):​c.1210G>C​(p.Glu404Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22473037).

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.1210G>C	p.Glu404Gln	missense	Exon 10 of 11	NP_002159.2
	IDH2	NM_001289910.1		c.1054G>C	p.Glu352Gln	missense	Exon 10 of 11	NP_001276839.1	P48735-2
	IDH2	NM_001290114.2		c.820G>C	p.Glu274Gln	missense	Exon 8 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.1210G>C	p.Glu404Gln	missense	Exon 10 of 11	ENSP00000331897.4	P48735-1
	IDH2	ENST00000864224.1		c.1294G>C	p.Glu432Gln	missense	Exon 11 of 12	ENSP00000534283.1
	IDH2	ENST00000864227.1		c.1279G>C	p.Glu427Gln	missense	Exon 11 of 12	ENSP00000534286.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251428 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461820 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	D-2-hydroxyglutaric aciduria 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.0060	B
Vest4		0.27
MutPred		0.38		Loss of ubiquitination at K400 (P = 0.0818)
MVP		0.59
MPC		0.51
ClinPred		0.047	T
GERP RS		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.33
gMVP		0.75

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: rs767090389; hg19: chr15-90628109;