rs369445642

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_002168.4(IDH2):c.23T>C(p.Val8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,365,148 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

IDH2
NM_002168.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1

Conservation

PhyloP100: -0.0680

Publications

5 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 links:

IDH2-DT (HGNC:53154): (IDH2 divergent transcript)

IDH2-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005317807).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00205 (310/151062) while in subpopulation AFR AF = 0.00691 (286/41384). AF 95% confidence interval is 0.00625. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 310 AD gene.

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.23T>C	p.Val8Ala	missense	Exon 1 of 11	NP_002159.2
IDH2	NM_001290114.2		c.-110T>C		5_prime_UTR	Exon 1 of 9	NP_001277043.1	B4DSZ6
IDH2-DT	NR_149130.1		n.237A>G		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDH2	ENST00000330062.8	TSL:1 MANE Select	c.23T>C	p.Val8Ala	missense	Exon 1 of 11	ENSP00000331897.4	P48735-1
IDH2	ENST00000864224.1		c.23T>C	p.Val8Ala	missense	Exon 1 of 12	ENSP00000534283.1
IDH2	ENST00000864227.1		c.23T>C	p.Val8Ala	missense	Exon 1 of 12	ENSP00000534286.1

Frequencies

GnomAD3 genomes

AF:

0.00206

AC:

311

AN:

150954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00695

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.0000965

AC:

AN:

72574

AF XY:

0.0000474

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.000221

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:

0.000169

AC:

205

AN:

1214086

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

595934

show subpopulations

African (AFR)

AF:

0.00660

AC:

167

AN:

25320

American (AMR)

AF:

0.000604

AC:

AN:

23166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20196

East Asian (EAS)

AF:

0.00

AC:

AN:

26130

South Asian (SAS)

AF:

0.00

AC:

AN:

57900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4112

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

981042

Other (OTH)

AF:

0.000478

AC:

AN:

48116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00205

AC:

310

AN:

151062

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

151

AN XY:

73808

show subpopulations

African (AFR)

AF:

0.00691

AC:

286

AN:

41384

American (AMR)

AF:

0.00132

AC:

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67632

Other (OTH)

AF:

0.00143

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.00244

ESP6500AA

AF:

0.00210

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000468

AC:

Asia WGS

AF:

0.000613

AC:

AN:

3276

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

D-2-hydroxyglutaric aciduria 2 (1)

IDH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.16

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

-0.068

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.44

REVEL

Benign

0.10

Sift

Benign

0.47

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.12

MVP

0.56

MPC

0.62

ClinPred

0.0048

GERP RS

0.98

PromoterAI

-0.072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.025

gMVP

0.31

Mutation Taster

=87/13

polymorphism

(source)

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over