2-208237174-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_005896.4(IDH1):c.1155-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,450,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: IDH1 NM_005896.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000008577
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.89

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-208237174-C-T is Benign according to our data. Variant chr2-208237174-C-T is described in ClinVar as [Benign]. Clinvar id is 744029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00397 (104/26182) while in subpopulation AFR AF= 0.0115 (98/8514). AF 95% confidence interval is 0.00967. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH1	NM_005896.4	c.1155-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000345146.7
IDH1	NM_001282386.1	c.1155-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
IDH1	NM_001282387.1	c.1155-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH1	ENST00000345146.7	c.1155-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005896.4	P1
IDH1	ENST00000415913.5	c.1155-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
IDH1	ENST00000446179.5	c.1155-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
IDH1	ENST00000484575.1	n.617-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 104 AN: 26104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00185

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: 0.000158

Gnomad OTH AF: 0.00410

GnomAD3 exomes AF: 0.000352 AC: 45 AN: 127982 Hom.: 0 AF XY: 0.000241 AC XY: 17 AN XY: 70592

Gnomad AFR exome AF: 0.00416

Gnomad AMR exome AF: 0.000223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000654

Gnomad OTH exome AF: 0.000305

GnomAD4 exome AF: 0.0000920 AC: 131 AN: 1423964 Hom.: 0 Cov.: 23 AF XY: 0.0000802 AC XY: 57 AN XY: 710588

Gnomad4 AFR exome AF: 0.00168

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000537

Gnomad4 OTH exome AF: 0.000135

GnomAD4 genome AF: 0.00397 AC: 104 AN: 26182 Hom.: 0 Cov.: 33 AF XY: 0.00402 AC XY: 49 AN XY: 12196

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000158

Gnomad4 OTH AF: 0.00394

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000756

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

Invitae

May 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.080
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000086
dbscSNV1_RF	Benign	0.0
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: rs201787135; hg19: chr2-209101898;