chr15-90084321-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002168.4(IDH2):​c.1304C>T​(p.Thr435Met) variant causes a missense change. The variant allele was found at a frequency of 0.00627 in 1,614,042 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0066 ( 52 hom. )

Consequence

IDH2
NM_002168.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 5.11
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009162426).
BP6
Variant 15-90084321-G-A is Benign according to our data. Variant chr15-90084321-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158664.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr15-90084321-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00358 (545/152278) while in subpopulation NFE AF= 0.00676 (460/68024). AF 95% confidence interval is 0.00625. There are 3 homozygotes in gnomad4. There are 237 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 545 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IDH2NM_002168.4 linkuse as main transcriptc.1304C>T p.Thr435Met missense_variant 11/11 ENST00000330062.8
IDH2NM_001289910.1 linkuse as main transcriptc.1148C>T p.Thr383Met missense_variant 11/11
IDH2NM_001290114.2 linkuse as main transcriptc.914C>T p.Thr305Met missense_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IDH2ENST00000330062.8 linkuse as main transcriptc.1304C>T p.Thr435Met missense_variant 11/111 NM_002168.4 P1P48735-1
IDH2ENST00000540499.2 linkuse as main transcriptc.1148C>T p.Thr383Met missense_variant 11/112 P48735-2
IDH2ENST00000559482.5 linkuse as main transcriptc.884C>T p.Thr295Met missense_variant 8/85
IDH2ENST00000560061.1 linkuse as main transcriptc.*929C>T 3_prime_UTR_variant, NMD_transcript_variant 9/92

Frequencies

GnomAD3 genomes
AF:
0.00358
AC:
545
AN:
152160
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00111
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00137
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00676
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00362
AC:
910
AN:
251056
Hom.:
5
AF XY:
0.00368
AC XY:
499
AN XY:
135728
show subpopulations
Gnomad AFR exome
AF:
0.000924
Gnomad AMR exome
AF:
0.00165
Gnomad ASJ exome
AF:
0.000596
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000948
Gnomad FIN exome
AF:
0.00228
Gnomad NFE exome
AF:
0.00646
Gnomad OTH exome
AF:
0.00343
GnomAD4 exome
AF:
0.00655
AC:
9579
AN:
1461764
Hom.:
52
Cov.:
31
AF XY:
0.00637
AC XY:
4634
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00116
Gnomad4 AMR exome
AF:
0.00168
Gnomad4 ASJ exome
AF:
0.000727
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00109
Gnomad4 FIN exome
AF:
0.00249
Gnomad4 NFE exome
AF:
0.00794
Gnomad4 OTH exome
AF:
0.00649
GnomAD4 genome
AF:
0.00358
AC:
545
AN:
152278
Hom.:
3
Cov.:
32
AF XY:
0.00318
AC XY:
237
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.00111
Gnomad4 AMR
AF:
0.00137
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.00676
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00575
Hom.:
8
Bravo
AF:
0.00363
TwinsUK
AF:
0.00809
AC:
30
ALSPAC
AF:
0.00675
AC:
26
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00663
AC:
57
ExAC
AF:
0.00374
AC:
454
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00660
EpiControl
AF:
0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024IDH2: BP4, BS2 -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 26, 2016- -
Enchondromatosis Uncertain:1
Uncertain significance, criteria provided, single submitterresearchBaylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine-- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 18, 2014- -
D-2-hydroxyglutaric aciduria 2 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 18, 2024- -
IDH2-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 29, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.38
T;T;.
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.41
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.0092
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.14
N;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.45
T
PROVEAN
Benign
0.29
N;N;N
REVEL
Benign
0.10
Sift
Benign
0.14
T;T;T
Sift4G
Benign
0.14
T;T;T
Polyphen
0.027
B;.;.
Vest4
0.27
MVP
0.74
MPC
0.65
ClinPred
0.012
T
GERP RS
2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.10
gMVP
0.72

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: rs118053940; hg19: chr15-90627553; COSMIC: COSV51561910; COSMIC: COSV51561910; API