rs146578303

Variant names:

• chr2-241755984-G-A
• rs146578303
• NM_152783.5:c.1276G>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_152783.5(D2HGDH):​c.1276G>A​(p.Ala426Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00716 in 1,603,256 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (66 hom.)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 5.84
• Publications: 15 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

ENSG00000234793 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.010284096).
• BP6: Variant 2-241755984-G-A is Benign according to our data. Variant chr2-241755984-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00609 (927/152310) while in subpopulation NFE AF = 0.00664 (452/68026). AF 95% confidence interval is 0.00614. There are 6 homozygotes in GnomAd4. There are 556 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.1276G>A	p.Ala426Thr	missense	Exon 9 of 10	NP_689996.4
	D2HGDH	NM_001287249.2		c.874G>A	p.Ala292Thr	missense	Exon 8 of 9	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.715G>A	p.Ala239Thr	missense	Exon 9 of 10	NP_001339753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.1276G>A	p.Ala426Thr	missense	Exon 9 of 10	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.*2512G>A		non_coding_transcript_exon	Exon 11 of 12	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000468064.5	TSL:1	n.1166G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152192 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00664

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00710 AC: 1749 AN: 246360 AF XY: 0.00710

Gnomad AFR exome AF: 0.000873

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00830

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0281

Gnomad NFE exome AF: 0.00780

Gnomad OTH exome AF: 0.00828

GnomAD4 exome AF: 0.00727 AC: 10545 AN: 1450946 Hom.: 66 Cov.: 36 AF XY: 0.00701 AC XY: 5048 AN XY: 719654

African (AFR) AF: 0.000873 AC: 29 AN: 33236

American (AMR) AF: 0.00200 AC: 89 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00828 AC: 215 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39350

South Asian (SAS) AF: 0.00226 AC: 194 AN: 85996

European-Finnish (FIN) AF: 0.0264 AC: 1376 AN: 52150

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.00742 AC: 8193 AN: 1104292

Other (OTH) AF: 0.00743 AC: 444 AN: 59794

GnomAD4 genome AF: 0.00609 AC: 927 AN: 152310 Hom.: 6 Cov.: 33 AF XY: 0.00747 AC XY: 556 AN XY: 74474

African (AFR) AF: 0.00137 AC: 57 AN: 41574

American (AMR) AF: 0.00268 AC: 41 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.0308 AC: 327 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00664 AC: 452 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00531 Hom.: 1

Bravo AF: 0.00387

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00757 AC: 65

ExAC AF: 0.00707 AC: 858

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00712

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	D-2-hydroxyglutaric aciduria 1 (3)
-	-	2	not specified (2)
-	-	1	D2HGDH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0020	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.61
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Polyphen		0.41	B
Vest4		0.82
MVP		0.89
MPC		0.39
ClinPred		0.025	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.87
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146578303; hg19: chr2-242695399; COSMIC: COSV100344692; COSMIC: COSV100344692;