rs77940364

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152783.5(D2HGDH):c.164G>A(p.Arg55Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,589,620 control chromosomes in the GnomAD database, including 72,410 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.27 ( 6006 hom., cov: 35)

Exomes 𝑓: 0.30 ( 66404 hom. )

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.906

Publications

25 publications found

Variant links:

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

D2HGDH links:

ENSG00000215692 (HGNC:):

ENSG00000215692 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0021398067).

BP6

Variant 2-241735388-G-A is Benign according to our data. Variant chr2-241735388-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.316 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
D2HGDH	NM_152783.5	MANE Select	c.164G>A	p.Arg55Gln	missense	Exon 2 of 10	NP_689996.4
D2HGDH	NM_001352824.2		c.-381G>A		5_prime_UTR	Exon 2 of 10	NP_001339753.1
D2HGDH	NM_001287249.2		c.-111+693G>A		intron	N/A	NP_001274178.1	B5MCV2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.164G>A	p.Arg55Gln	missense	Exon 2 of 10	ENSP00000315351.4	Q8N465-1
D2HGDH	ENST00000436747.5	TSL:1	n.164G>A		non_coding_transcript_exon	Exon 2 of 12	ENSP00000400212.1	F8WCF9
D2HGDH	ENST00000951632.1		c.164G>A	p.Arg55Gln	missense	Exon 2 of 12	ENSP00000621691.1

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41593

AN:

152144

Hom.:

6005

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.382

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.298

Gnomad FIN

AF:

0.298

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.273

GnomAD2 exomes

AF:

0.278

AC:

55268

AN:

198738

AF XY:

0.286

show subpopulations

Gnomad AFR exome

AF:

0.203

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.374

Gnomad EAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.283

Gnomad NFE exome

AF:

0.319

Gnomad OTH exome

AF:

0.293

GnomAD4 exome

AF:

0.300

AC:

431924

AN:

1437358

Hom.:

66404

Cov.:

AF XY:

0.302

AC XY:

215402

AN XY:

713498

show subpopulations

African (AFR)

AF:

0.198

AC:

6615

AN:

33342

American (AMR)

AF:

0.198

AC:

7885

AN:

39842

Ashkenazi Jewish (ASJ)

AF:

0.377

AC:

9676

AN:

25646

East Asian (EAS)

AF:

0.162

AC:

6302

AN:

38874

South Asian (SAS)

AF:

0.297

AC:

24808

AN:

83654

European-Finnish (FIN)

AF:

0.294

AC:

13884

AN:

47152

Middle Eastern (MID)

AF:

0.346

AC:

1974

AN:

5704

European-Non Finnish (NFE)

AF:

0.311

AC:

343221

AN:

1103526

Other (OTH)

AF:

0.295

AC:

17559

AN:

59618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20236

40472

60709

80945

101181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11078

22156

33234

44312

55390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.273

AC:

41597

AN:

152262

Hom.:

6006

Cov.:

AF XY:

0.271

AC XY:

20205

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.206

AC:

8578

AN:

41570

American (AMR)

AF:

0.229

AC:

3499

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.382

AC:

1327

AN:

3472

East Asian (EAS)

AF:

0.151

AC:

781

AN:

5172

South Asian (SAS)

AF:

0.298

AC:

1437

AN:

4826

European-Finnish (FIN)

AF:

0.298

AC:

3163

AN:

10604

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.320

AC:

21739

AN:

67992

Other (OTH)

AF:

0.273

AC:

578

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1593

3186

4780

6373

7966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.307

Hom.:

11160

Bravo

AF:

0.261

TwinsUK

AF:

0.316

AC:

1172

ALSPAC

AF:

0.300

AC:

1158

ESP6500AA

AF:

0.192

AC:

788

ESP6500EA

AF:

0.313

AC:

2638

ExAC

AF:

0.258

AC:

30457

Asia WGS

AF:

0.214

AC:

745

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

D-2-hydroxyglutaric aciduria 1 (3)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.2

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.043

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.86

PhyloP100

-0.91

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.090

REVEL

Benign

0.14

Sift

Benign

0.64

Sift4G

Benign

0.57

Polyphen

0.032

Vest4

0.032

MPC

0.43

ClinPred

0.0048

GERP RS

-6.4

Varity_R

0.036

gMVP

0.48

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over