rs190078206

Positions:

• chr15-90085317-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002168.4(IDH2):​c.1038C>T​(p.Ala346Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,552,396 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: IDH2 NM_002168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 15-90085317-G-A is Benign according to our data. Variant chr15-90085317-G-A is described in ClinVar as [Benign]. Clinvar id is 211173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000644 (98/152148) while in subpopulation EAS AF= 0.011 (57/5164). AF 95% confidence interval is 0.00875. There are 1 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH2	NM_002168.4	c.1038C>T	p.Ala346Ala	synonymous_variant	8/11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.882C>T	p.Ala294Ala	synonymous_variant	8/11		NP_001276839.1
IDH2	NM_001290114.2	c.648C>T	p.Ala216Ala	synonymous_variant	6/9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.1038C>T	p.Ala346Ala	synonymous_variant	8/11	1	NM_002168.4	ENSP00000331897.4

Frequencies

GnomAD3 genomes AF: 0.000645 AC: 98 AN: 152030 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000988 AC: 156 AN: 157824 Hom.: 0 AF XY: 0.000902 AC XY: 75 AN XY: 83124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0110

Gnomad SAS exome AF: 0.0000870

Gnomad FIN exome AF: 0.00137

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.000448 AC: 628 AN: 1400248 Hom.: 4 Cov.: 32 AF XY: 0.000453 AC XY: 313 AN XY: 690796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.000277

Gnomad4 FIN exome AF: 0.00177

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.000982

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74360

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000525

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 25, 2017

- -

D-2-hydroxyglutaric aciduria 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.5
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs190078206; hg19: chr15-90628549;