15-90088606-C-T

Position:

• chr15-90088606-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_002168.4(IDH2):​c.515G>A​(p.Arg172Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,risk factor (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic; risk factor no assertion criteria provided P:5 O:2
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity IDHP_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 15-90088606-C-T is Pathogenic according to our data. Variant chr15-90088606-C-T is described in ClinVar as [Likely_pathogenic, risk_factor]. Clinvar id is 375987.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH2	NM_002168.4	c.515G>A	p.Arg172Lys	missense_variant	4/11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.359G>A	p.Arg120Lys	missense_variant	4/11		NP_001276839.1
IDH2	NM_001290114.2	c.125G>A	p.Arg42Lys	missense_variant	2/9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.515G>A	p.Arg172Lys	missense_variant	4/11	1	NM_002168.4	ENSP00000331897	P1
IDH2	ENST00000540499.2	c.359G>A	p.Arg120Lys	missense_variant	4/11	2		ENSP00000446147
IDH2	ENST00000559482.5	c.208-104G>A		intron_variant		5		ENSP00000453016
IDH2	ENST00000560061.1	c.*140G>A		3_prime_UTR_variant, NMD_transcript_variant	2/9	2		ENSP00000453254

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic; risk factor

Submissions summary: Pathogenic:5 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Brainstem glioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Acute myeloid leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Myelodysplastic syndrome Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Acute myocardial infarction Other:1

risk factor, no assertion criteria provided

case-control

Clinical Pathology, Faculty of Medicine, Tanta University

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.88		Gain of methylation at R172 (P = 0.0071);.;
MVP		0.82
MPC		1.4
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.86
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913503; hg19: chr15-90631838; COSMIC: COSV57468734;