2-208248572-C-T

Variant names:

• chr2-208248572-C-T
• rs73070954
• NM_005896.4:c.211G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005896.4(IDH1):​c.211G>A​(p.Val71Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,614,100 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V71L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (46 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (41 hom.)
• Consequence: IDH1 NM_005896.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.845
• Publications: 25 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006154537).
• BP6: Variant 2-208248572-C-T is Benign according to our data. Variant chr2-208248572-C-T is described in ClinVar as Benign. ClinVar VariationId is 134516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2024/152286) while in subpopulation AFR AF = 0.0449 (1867/41556). AF 95% confidence interval is 0.0432. There are 46 homozygotes in GnomAd4. There are 956 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2024 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH1	NM_005896.4	MANE Select	c.211G>A	p.Val71Ile	missense	Exon 4 of 10	NP_005887.2
	IDH1	NM_001282386.1		c.211G>A	p.Val71Ile	missense	Exon 4 of 10	NP_001269315.1
	IDH1	NM_001282387.1		c.211G>A	p.Val71Ile	missense	Exon 4 of 10	NP_001269316.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH1	ENST00000345146.7	TSL:1 MANE Select	c.211G>A	p.Val71Ile	missense	Exon 4 of 10	ENSP00000260985.2
	IDH1	ENST00000415913.5	TSL:1	c.211G>A	p.Val71Ile	missense	Exon 4 of 10	ENSP00000390265.1
	IDH1	ENST00000446179.5	TSL:1	c.211G>A	p.Val71Ile	missense	Exon 4 of 10	ENSP00000410513.1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2019 AN: 152168 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00347 AC: 873 AN: 251470 AF XY: 0.00258

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00148 AC: 2163 AN: 1461814 Hom.: 41 Cov.: 32 AF XY: 0.00131 AC XY: 951 AN XY: 727220

African (AFR) AF: 0.0456 AC: 1526 AN: 33480

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

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: 0.000264 AC: 294 AN: 1111942

Other (OTH) AF: 0.00310 AC: 187 AN: 60390

GnomAD4 genome AF: 0.0133 AC: 2024 AN: 152286 Hom.: 46 Cov.: 33 AF XY: 0.0128 AC XY: 956 AN XY: 74462

African (AFR) AF: 0.0449 AC: 1867 AN: 41556

American (AMR) AF: 0.00713 AC: 109 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68036

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00737 Hom.: 15

Bravo AF: 0.0150

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00421 AC: 511

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.4
DANN	Benign	0.18
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.32	N
PhyloP100		0.84
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.36
MPC		0.14
ClinPred		0.0041	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.54
Mutation Taster		=97/3	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: rs73070954; hg19: chr2-209113296; COSMIC: COSV61618577;