15-90088607-T-C

Variant names:

• chr15-90088607-T-C
• rs1057519906
• NM_002168.4:c.514A>G
• IDH2 p.Arg172Gly

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Moderate

The NM_002168.4(IDH2):​c.514A>G​(p.Arg172Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005902248: "In support of this prediction, functional studies using cell lines show that this variant disrupts the resulting enzyme's ability to catalyze conversion of isocitrate to alpha-ketoglutarate and results in a gain of function to IDH2 as indicated by production of 2HG (2-hydroxyglutarate), and leads to activation of HIF-1-alpha signaling and nuclear accumulation of beta-catenin in cell culture (Fu Yet al., PMID:22309944" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 1.56
• Publications: 169 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005902248: "In support of this prediction, functional studies using cell lines show that this variant disrupts the resulting enzyme's ability to catalyze conversion of isocitrate to alpha-ketoglutarate and results in a gain of function to IDH2 as indicated by production of 2HG (2-hydroxyglutarate), and leads to activation of HIF-1-alpha signaling and nuclear accumulation of beta-catenin in cell culture (Fu Yet al., PMID: 22309944; Jin G et al., PMID: 21326614)."
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-90088605-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2691259.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 15-90088607-T-C is Pathogenic according to our data. Variant chr15-90088607-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376439.Status of the report is criteria_provided_single_submitter, 1 stars.

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.514A>G	p.Arg172Gly	missense	Exon 4 of 11	NP_002159.2
	IDH2	NM_001289910.1		c.358A>G	p.Arg120Gly	missense	Exon 4 of 11	NP_001276839.1	P48735-2
	IDH2	NM_001290114.2		c.124A>G	p.Arg42Gly	missense	Exon 2 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.514A>G	p.Arg172Gly	missense	Exon 4 of 11	ENSP00000331897.4	P48735-1
	IDH2	ENST00000864224.1		c.598A>G	p.Arg200Gly	missense	Exon 5 of 12	ENSP00000534283.1
	IDH2	ENST00000864227.1		c.583A>G	p.Arg195Gly	missense	Exon 5 of 12	ENSP00000534286.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Maffucci syndrome (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	0.067
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		1.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.99

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057519906;

hg19: chr15-90631839;

COSMIC: COSV57468989;