rs1057519906

Variant names:

• chr15-90088607-T-A
• rs1057519906
• NM_002168.4:c.514A>T

Your query was ambiguous. Multiple possible variants found:

• chr15-90088607-T-A
• chr15-90088607-T-C
• chr15-90088607-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_002168.4(IDH2):​c.514A>T​(p.Arg172Trp) 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 risk factor (no stars). 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: risk factor no assertion criteria provided 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: Likely_pathogenic. The variant received 8 ACMG points.

• 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, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH2	NM_002168.4	c.514A>T	p.Arg172Trp	missense_variant	Exon 4 of 11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.358A>T	p.Arg120Trp	missense_variant	Exon 4 of 11		NP_001276839.1
IDH2	NM_001290114.2	c.124A>T	p.Arg42Trp	missense_variant	Exon 2 of 9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.514A>T	p.Arg172Trp	missense_variant	Exon 4 of 11	1	NM_002168.4	ENSP00000331897.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Acute myocardial infarction Other:1

-

Clinical Pathology, Faculty of Medicine, Tanta University

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Benign	0.067
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.2	H;.
PhyloP100		1.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.89		Gain of sheet (P = 0.0344);.;
MVP		0.87
MPC		1.5
ClinPred		1.0	D
GERP RS		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.98

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: rs1057519906; hg19: chr15-90631839; COSMIC: COSV57468942;