rs148813816

Variant names:

• chr2-241735525-G-A
• rs148813816
• NM_152783.5:c.292+9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152783.5(D2HGDH):​c.292+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,603,698 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (146 hom., cov: 35)
  • Exomes 𝑓: 0.0024 (110 hom.)
• Consequence: D2HGDH NM_152783.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.08
• Publications: 0 publications found

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]

D2HGDH Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• D-2-hydroxyglutaric aciduria 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• D-2-hydroxyglutaric aciduria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000215692 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-241735525-G-A is Benign according to our data. Variant chr2-241735525-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0769 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152783.5. 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
	D2HGDH	NM_152783.5	MANE Select	c.292+9G>A		intron	N/A	NP_689996.4
	D2HGDH	NM_001287249.2		c.-111+830G>A		intron	N/A	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.-253+9G>A		intron	N/A	NP_001339753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.292+9G>A		intron	N/A	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.292+9G>A		intron	N/A	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000951632.1		c.292+9G>A		intron	N/A	ENSP00000621691.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3484 AN: 152236 Hom.: 143 Cov.: 35

Gnomad AFR AF: 0.0790

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.00549 AC: 1265 AN: 230502 AF XY: 0.00393

Gnomad AFR exome AF: 0.0756

Gnomad AMR exome AF: 0.00372

Gnomad ASJ exome AF: 0.000819

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000201

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00240 AC: 3477 AN: 1451344 Hom.: 110 Cov.: 39 AF XY: 0.00201 AC XY: 1449 AN XY: 722572

African (AFR) AF: 0.0828 AC: 2770 AN: 33446

American (AMR) AF: 0.00441 AC: 197 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.000996 AC: 26 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43762

Middle Eastern (MID) AF: 0.00356 AC: 20 AN: 5624

European-Non Finnish (NFE) AF: 0.000118 AC: 131 AN: 1111638

Other (OTH) AF: 0.00530 AC: 319 AN: 60242

GnomAD4 genome AF: 0.0230 AC: 3500 AN: 152354 Hom.: 146 Cov.: 35 AF XY: 0.0214 AC XY: 1594 AN XY: 74506

African (AFR) AF: 0.0791 AC: 3290 AN: 41584

American (AMR) AF: 0.00927 AC: 142 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68030

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.00819 Hom.: 25

Bravo AF: 0.0258

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs148813816; hg19: chr2-242674940;