2-241734689-A-G

Variant summary

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

The NM_152783.5(D2HGDH):c.-99A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 151,422 control chromosomes in the GnomAD database, including 38,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.70 (38336 hom., cov: 33)
  • Exomes 𝑓: 0.67 (76 hom.)
• Consequence: D2HGDH NM_152783.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0930

Genes affected

D2HGDH (HGNC:28358): (D-2-hydroxyglutarate dehydrogenase) This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-241734689-A-G is Benign according to our data. Variant chr2-241734689-A-G is described in ClinVar as [Benign]. Clinvar id is 335307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
D2HGDH	NM_152783.5	c.-99A>G		5_prime_UTR_variant	1/10	ENST00000321264.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
D2HGDH	ENST00000321264.9	c.-99A>G		5_prime_UTR_variant	1/10	1	NM_152783.5	P1
	ENST00000400768.2			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106041 AN: 150978 Hom.: 38277 Cov.: 33

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.753

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.703

GnomAD4 exome AF: 0.670 AC: 225 AN: 336 Hom.: 76 Cov.: 0 AF XY: 0.672 AC XY: 164 AN XY: 244

Gnomad4 AFR exome AF: 0.875

Gnomad4 AMR exome AF: 0.875

Gnomad4 ASJ exome AF: 0.600

Gnomad4 EAS exome AF: 0.786

Gnomad4 SAS exome AF: 0.667

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.659

Gnomad4 OTH exome AF: 0.714

GnomAD4 genome AF: 0.703 AC: 106151 AN: 151086 Hom.: 38336 Cov.: 33 AF XY: 0.705 AC XY: 51980 AN XY: 73778

Gnomad4 AFR AF: 0.864

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.694

Gnomad4 EAS AF: 0.711

Gnomad4 SAS AF: 0.573

Gnomad4 FIN AF: 0.709

Gnomad4 NFE AF: 0.599

Gnomad4 OTH AF: 0.701

Alfa AF: 0.628 Hom.: 7069

Bravo AF: 0.715

Asia WGS AF: 0.657 AC: 2223 AN: 3386

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	11
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7370843; hg19: chr2-242674104;