rs144712130

Variant names:

• chr15-90088692-C-G
• rs144712130
• NM_002168.4:c.429G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-90088692-C-G
• chr15-90088692-C-A
• chr15-90088692-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002168.4(IDH2):​c.429G>C​(p.Leu143Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,614,124 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L143L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (12 hom., cov: 31)
  • Exomes 𝑓: 0.00076 (18 hom.)
• Consequence: IDH2 NM_002168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.93
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-90088692-C-G is Benign according to our data. Variant chr15-90088692-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00759 (1156/152242) while in subpopulation AFR AF = 0.0262 (1089/41524). AF 95% confidence interval is 0.0249. There are 12 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1156 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH2	NM_002168.4	MANE Select	c.429G>C	p.Leu143Leu	synonymous	Exon 4 of 11	NP_002159.2
	IDH2	NM_001289910.1		c.273G>C	p.Leu91Leu	synonymous	Exon 4 of 11	NP_001276839.1	P48735-2
	IDH2	NM_001290114.2		c.39G>C	p.Leu13Leu	synonymous	Exon 2 of 9	NP_001277043.1	B4DSZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH2	ENST00000330062.8	TSL:1 MANE Select	c.429G>C	p.Leu143Leu	synonymous	Exon 4 of 11	ENSP00000331897.4	P48735-1
	IDH2	ENST00000864224.1		c.513G>C	p.Leu171Leu	synonymous	Exon 5 of 12	ENSP00000534283.1
	IDH2	ENST00000864227.1		c.498G>C	p.Leu166Leu	synonymous	Exon 5 of 12	ENSP00000534286.1

Frequencies

GnomAD3 genomes AF: 0.00759 AC: 1154 AN: 152124 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00220 AC: 554 AN: 251496 AF XY: 0.00172

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000763 AC: 1115 AN: 1461882 Hom.: 18 Cov.: 33 AF XY: 0.000674 AC XY: 490 AN XY: 727244

African (AFR) AF: 0.0266 AC: 892 AN: 33478

American (AMR) AF: 0.00181 AC: 81 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1112002

Other (OTH) AF: 0.00177 AC: 107 AN: 60396

GnomAD4 genome AF: 0.00759 AC: 1156 AN: 152242 Hom.: 12 Cov.: 31 AF XY: 0.00743 AC XY: 553 AN XY: 74430

African (AFR) AF: 0.0262 AC: 1089 AN: 41524

American (AMR) AF: 0.00340 AC: 52 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.000784 Hom.: 0

Bravo AF: 0.00896

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	D-2-hydroxyglutaric aciduria 2 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.059
DANN	Benign	0.39
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs144712130; hg19: chr15-90631924;