15-90091367-C-T

Variant names:

• chr15-90091367-C-T
• rs8030346
• NM_002168.4:c.207+186G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002168.4(IDH2):​c.207+186G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 152,118 control chromosomes in the GnomAD database, including 27,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.60 (27765 hom., cov: 33)
• Consequence: IDH2 NM_002168.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -8.58
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 15-90091367-C-T is Benign according to our data. Variant chr15-90091367-C-T is described in ClinVar as Benign. ClinVar VariationId is 1237553.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH2	NM_002168.4	c.207+186G>A		intron_variant	Intron 2 of 10	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.51+186G>A		intron_variant	Intron 2 of 10		NP_001276839.1
IDH2	NM_001290114.2	c.-17-2620G>A		intron_variant	Intron 1 of 8		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.207+186G>A		intron_variant	Intron 2 of 10	1	NM_002168.4	ENSP00000331897.4
IDH2	ENST00000540499.2	c.51+186G>A		intron_variant	Intron 2 of 10	2		ENSP00000446147.2
IDH2	ENST00000559482.5	c.207+186G>A		intron_variant	Intron 2 of 7	5		ENSP00000453016.1
IDH2	ENST00000560061.1	n.116-2620G>A		intron_variant	Intron 1 of 8	2		ENSP00000453254.1

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90747 AN: 152000 Hom.: 27743 Cov.: 33

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.550

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.597 AC: 90809 AN: 152118 Hom.: 27765 Cov.: 33 AF XY: 0.587 AC XY: 43644 AN XY: 74358

African (AFR) AF: 0.718 AC: 29806 AN: 41502

American (AMR) AF: 0.478 AC: 7310 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1798 AN: 3466

East Asian (EAS) AF: 0.379 AC: 1962 AN: 5172

South Asian (SAS) AF: 0.415 AC: 2003 AN: 4826

European-Finnish (FIN) AF: 0.550 AC: 5821 AN: 10576

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.592 AC: 40205 AN: 67968

Other (OTH) AF: 0.548 AC: 1159 AN: 2114

Alfa AF: 0.577 Hom.: 36741

Bravo AF: 0.599

Asia WGS AF: 0.393 AC: 1371 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.072
DANN	Benign	0.66
PhyloP100		-8.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs8030346; hg19: chr15-90634599;