chr15-90084321-G-A

Variant names:

• chr15-90084321-G-A
• rs118053940
• NM_002168.4:c.1304C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 16/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 5.11
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 158664.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 545 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH2	NM_002168.4	MANE Select	c.1304C>T	p.Thr435Met	missense	Exon 11 of 11	NP_002159.2
	IDH2	NM_001289910.1		c.1148C>T	p.Thr383Met	missense	Exon 11 of 11	NP_001276839.1
	IDH2	NM_001290114.2		c.914C>T	p.Thr305Met	missense	Exon 9 of 9	NP_001277043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH2	ENST00000330062.8	TSL:1 MANE Select	c.1304C>T	p.Thr435Met	missense	Exon 11 of 11	ENSP00000331897.4
	IDH2	ENST00000540499.2	TSL:2	c.1148C>T	p.Thr383Met	missense	Exon 11 of 11	ENSP00000446147.2
	IDH2	ENST00000559482.5	TSL:5	c.884C>T	p.Thr295Met	missense	Exon 8 of 8	ENSP00000453016.1

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 545 AN: 152160 Hom.: 3 Cov.: 32

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

GnomAD2 exomes AF: 0.00362 AC: 910 AN: 251056 AF XY: 0.00368

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 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

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00168 AC: 75 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86236

European-Finnish (FIN) AF: 0.00249 AC: 133 AN: 53396

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5748

European-Non Finnish (NFE) AF: 0.00794 AC: 8824 AN: 1111960

Other (OTH) AF: 0.00649 AC: 392 AN: 60388

GnomAD4 genome AF: 0.00358 AC: 545 AN: 152278 Hom.: 3 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74448

African (AFR) AF: 0.00111 AC: 46 AN: 41558

American (AMR) AF: 0.00137 AC: 21 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00676 AC: 460 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00534 Hom.: 9

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	D-2-hydroxyglutaric aciduria 2 (1)
-	1	-	Enchondromatosis (1)
-	-	1	IDH2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		5.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.10
Sift	Benign	0.14	T
Sift4G	Benign	0.14	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
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

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