Genetic Variant IDH2:p.Thr350Thr (chr15-90085305-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_002168.4(IDH2):c.1050C>G(p.Thr350Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T350T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IDH2
NM_002168.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.17

Publications

22 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP7

Synonymous conserved (PhyloP=-5.17 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH2	NM_002168.4 link	c.1050C>G	p.Thr350Thr	synonymous_variant	Exon 8 of 11	ENST00000330062.8	NP_002159.2	P48735-1
IDH2	NM_001289910.1 link	c.894C>G	p.Thr298Thr	synonymous_variant	Exon 8 of 11		NP_001276839.1	P48735-2
IDH2	NM_001290114.2 link	c.660C>G	p.Thr220Thr	synonymous_variant	Exon 6 of 9		NP_001277043.1	P48735B4DSZ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8 link	c.1050C>G	p.Thr350Thr	synonymous_variant	Exon 8 of 11	1	NM_002168.4	ENSP00000331897.4		P48735-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000638

AC:

AN:

156770

AF XY:

0.0000121

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399732

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690528

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31626

American (AMR)

AF:

0.00

AC:

AN:

35728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25172

East Asian (EAS)

AF:

0.00

AC:

AN:

35798

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079238

Other (OTH)

AF:

0.00

AC:

AN:

58012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.018

(source)

DANN

Benign

0.54

PhyloP100

-5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

15-90085305-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over