2-208238771-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005896.4(IDH1):c.1154+300C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0588 in 152,164 control chromosomes in the GnomAD database, including 325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.059 (325 hom., cov: 33)
• Consequence: IDH1 NM_005896.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.251

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-208238771-G-A is Benign according to our data. Variant chr2-208238771-G-A is described in ClinVar as [Benign]. Clinvar id is 1228093.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH1	NM_005896.4	c.1154+300C>T		intron_variant		ENST00000345146.7
IDH1	NM_001282386.1	c.1154+300C>T		intron_variant
IDH1	NM_001282387.1	c.1154+300C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH1	ENST00000345146.7	c.1154+300C>T		intron_variant		1	NM_005896.4	P1
IDH1	ENST00000415913.5	c.1154+300C>T		intron_variant		1		P1
IDH1	ENST00000446179.5	c.1154+300C>T		intron_variant		1		P1
IDH1	ENST00000484575.1	n.616+300C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0588 AC: 8939 AN: 152046 Hom.: 325 Cov.: 33

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0913

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0436

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0566

Gnomad OTH AF: 0.0589

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0588 AC: 8946 AN: 152164 Hom.: 325 Cov.: 33 AF XY: 0.0572 AC XY: 4253 AN XY: 74384

Gnomad4 AFR AF: 0.0786

Gnomad4 AMR AF: 0.0566

Gnomad4 ASJ AF: 0.0913

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.0432

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.0566

Gnomad4 OTH AF: 0.0583

Alfa AF: 0.0568 Hom.: 30

Bravo AF: 0.0607

Asia WGS AF: 0.0460 AC: 162 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.2
Dann	Benign	0.61

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: rs9646838; hg19: chr2-209103495;