chr15-90084859-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002168.4(IDH2):​c.1228G>A​(p.Ala410Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IDH2
NM_002168.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.674
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11810458).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IDH2NM_002168.4 linkuse as main transcriptc.1228G>A p.Ala410Thr missense_variant 10/11 ENST00000330062.8
IDH2NM_001289910.1 linkuse as main transcriptc.1072G>A p.Ala358Thr missense_variant 10/11
IDH2NM_001290114.2 linkuse as main transcriptc.838G>A p.Ala280Thr missense_variant 8/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IDH2ENST00000330062.8 linkuse as main transcriptc.1228G>A p.Ala410Thr missense_variant 10/111 NM_002168.4 P1P48735-1
IDH2ENST00000540499.2 linkuse as main transcriptc.1072G>A p.Ala358Thr missense_variant 10/112 P48735-2
IDH2ENST00000559482.5 linkuse as main transcriptc.851+142G>A intron_variant 5
IDH2ENST00000560061.1 linkuse as main transcriptc.*853G>A 3_prime_UTR_variant, NMD_transcript_variant 8/92

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251410
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
6.84e-7
AC:
1
AN:
1461798
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
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.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 04, 2024The c.1228G>A (p.A410T) alteration is located in exon 10 (coding exon 10) of the IDH2 gene. This alteration results from a G to A substitution at nucleotide position 1228, causing the alanine (A) at amino acid position 410 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
22
DANN
Benign
0.87
DEOGEN2
Benign
0.30
T;.
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.15
N
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-0.28
N;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.20
N;N
REVEL
Benign
0.14
Sift
Benign
0.41
T;T
Sift4G
Benign
0.39
T;T
Polyphen
0.0010
B;.
Vest4
0.18
MutPred
0.30
Loss of ubiquitination at K413 (P = 0.1166);.;
MVP
0.46
MPC
0.50
ClinPred
0.064
T
GERP RS
4.6
Varity_R
0.17
gMVP
0.55

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1344799848; hg19: chr15-90628091; API