rs1057519736

Positions:

• chr15-90088605-C-A
• chr15-90088605-C-G
• chr15-90088605-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.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).

• 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

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, 0.981
• PP5: Variant 15-90088605-C-A is Pathogenic according to our data. Variant chr15-90088605-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2691259.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.516G>T	p.Arg172Ser	missense_variant	4/11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.360G>T	p.Arg120Ser	missense_variant	4/11		NP_001276839.1
IDH2	NM_001290114.2	c.126G>T	p.Arg42Ser	missense_variant	2/9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.516G>T	p.Arg172Ser	missense_variant	4/11	1	NM_002168.4	ENSP00000331897	P1
IDH2	ENST00000540499.2	c.360G>T	p.Arg120Ser	missense_variant	4/11	2		ENSP00000446147
IDH2	ENST00000559482.5	c.208-103G>T		intron_variant		5		ENSP00000453016
IDH2	ENST00000560061.1	c.*141G>T		3_prime_UTR_variant, NMD_transcript_variant	2/9	2		ENSP00000453254

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

Pathogenic, no assertion criteria provided

clinical testing

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

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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;.
MutationTaster	Benign	1.0	D;D;D;D
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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-90631837; COSMIC: COSV57468910;