rs587778402

Variant names:

• chr2-208243503-A-C
• rs587778402
• NM_005896.4:c.622T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-208243503-A-C
• chr2-208243503-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005896.4(IDH1):​c.622T>G​(p.Tyr208Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y208H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDH1 NM_005896.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• Publications: 0 publications found

Genes affected

IDH1 (HGNC:5382): (isocitrate dehydrogenase (NADP(+)) 1) 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 cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

IDH1 Gene-Disease associations (from GenCC):

• Maffucci syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005896.4. 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
	IDH1	NM_005896.4	MANE Select	c.622T>G	p.Tyr208Asp	missense	Exon 6 of 10	NP_005887.2
	IDH1	NM_001282386.1		c.622T>G	p.Tyr208Asp	missense	Exon 6 of 10	NP_001269315.1
	IDH1	NM_001282387.1		c.622T>G	p.Tyr208Asp	missense	Exon 6 of 10	NP_001269316.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH1	ENST00000345146.7	TSL:1 MANE Select	c.622T>G	p.Tyr208Asp	missense	Exon 6 of 10	ENSP00000260985.2
	IDH1	ENST00000415913.5	TSL:1	c.622T>G	p.Tyr208Asp	missense	Exon 6 of 10	ENSP00000390265.1
	IDH1	ENST00000446179.5	TSL:1	c.622T>G	p.Tyr208Asp	missense	Exon 6 of 10	ENSP00000410513.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.70		Loss of catalytic residue at Y208 (P = 0.0055)
MVP		0.97
MPC		0.98
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.95
Mutation Taster		=10/90	disease causing

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: rs587778402; hg19: chr2-209108227;