Genetic Variant IDH2:p.His420Pro (chr15-90084828-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002168.4(IDH2):c.1259A>C(p.His420Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H420L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

IDH2
NM_002168.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.00

Publications

0 publications found

Variant links:

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

IDH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDH2	NM_002168.4	MANE Select	c.1259A>C	p.His420Pro	missense	Exon 10 of 11	NP_002159.2
IDH2	NM_001289910.1		c.1103A>C	p.His368Pro	missense	Exon 10 of 11	NP_001276839.1	P48735-2
IDH2	NM_001290114.2		c.869A>C	p.His290Pro	missense	Exon 8 of 9	NP_001277043.1	B4DSZ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDH2	ENST00000330062.8	TSL:1 MANE Select	c.1259A>C	p.His420Pro	missense	Exon 10 of 11	ENSP00000331897.4	P48735-1
IDH2	ENST00000864224.1		c.1343A>C	p.His448Pro	missense	Exon 11 of 12	ENSP00000534283.1
IDH2	ENST00000864227.1		c.1328A>C	p.His443Pro	missense	Exon 11 of 12	ENSP00000534286.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.76

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

3.1

PhyloP100

8.0

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.72

Sift

Uncertain

0.012

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.72

MutPred

0.40

Loss of catalytic residue at H420 (P = 0.0123)

MVP

0.90

MPC

1.8

ClinPred

1.0

GERP RS

5.4

Varity_R

0.94

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over