rs61737003

Positions:

• chr15-90085359-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002168.4(IDH2):​c.996C>T​(p.Ser332=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,557,252 control chromosomes in the GnomAD database, including 1,945 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (915 hom., cov: 32)
  • Exomes 𝑓: 0.020 (1030 hom.)
• Consequence: IDH2 NM_002168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.13

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=-0.8).
• BP6: Variant 15-90085359-G-A is Benign according to our data. Variant chr15-90085359-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90085359-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH2	NM_002168.4	c.996C>T	p.Ser332=	synonymous_variant	8/11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.840C>T	p.Ser280=	synonymous_variant	8/11		NP_001276839.1
IDH2	NM_001290114.2	c.606C>T	p.Ser202=	synonymous_variant	6/9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.996C>T	p.Ser332=	synonymous_variant	8/11	1	NM_002168.4	ENSP00000331897	P1
IDH2	ENST00000540499.2	c.840C>T	p.Ser280=	synonymous_variant	8/11	2		ENSP00000446147
IDH2	ENST00000559482.5	c.669C>T	p.Ser223=	synonymous_variant	6/8	5		ENSP00000453016
IDH2	ENST00000560061.1	c.*621C>T		3_prime_UTR_variant, NMD_transcript_variant	6/9	2		ENSP00000453254

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10918 AN: 152066 Hom.: 906 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0632

GnomAD3 exomes AF: 0.0282 AC: 4639 AN: 164566 Hom.: 266 AF XY: 0.0242 AC XY: 2102 AN XY: 86964

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.0000806

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.0263

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0244

GnomAD4 exome AF: 0.0201 AC: 28254 AN: 1405068 Hom.: 1030 Cov.: 32 AF XY: 0.0194 AC XY: 13434 AN XY: 693674

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.0257

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.000136

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0304

GnomAD4 genome AF: 0.0720 AC: 10951 AN: 152184 Hom.: 915 Cov.: 32 AF XY: 0.0701 AC XY: 5217 AN XY: 74394

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.0403

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.0268

Gnomad4 NFE AF: 0.0174

Gnomad4 OTH AF: 0.0620

Alfa AF: 0.0394 Hom.: 217

Bravo AF: 0.0798

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

D-2-hydroxyglutaric aciduria 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.035
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61737003; hg19: chr15-90628591; COSMIC: COSV51561820; COSMIC: COSV51561820;