rs1057519736

Variant names:

• chr15-90088605-C-A
• rs1057519736
• NM_002168.4:c.516G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-90088605-C-A
• chr15-90088605-C-G
• chr15-90088605-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_002168.4(IDH2):​c.516G>T​(p.Arg172Ser) 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 Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.829
• Publications: 4 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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-90088607-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376439.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 15-90088605-C-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH2	NM_002168.4	c.516G>T	p.Arg172Ser	missense_variant	Exon 4 of 11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.360G>T	p.Arg120Ser	missense_variant	Exon 4 of 11		NP_001276839.1
IDH2	NM_001290114.2	c.126G>T	p.Arg42Ser	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.516G>T	p.Arg172Ser	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Vascular malformation Pathogenic:1

-

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.47	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	4.2	H;.
PhyloP100		-0.83
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.91		Gain of disorder (P = 0.0759);.;
MVP		0.69
MPC		1.5
ClinPred		1.0	D
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=5/95	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: rs1057519736; hg19: chr15-90631837; COSMIC: COSV57468910;