2-241751260-G-A

Variant names:

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.1012G>A(p.Val338Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,613,708 control chromosomes in the GnomAD database, including 53,154 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 (★★).

Frequency

Genomes: 𝑓 0.26 ( 5167 hom., cov: 33)

Exomes 𝑓: 0.25 ( 47987 hom. )

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.63

Publications

44 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):

D-2-hydroxyglutaric aciduria 1
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
D-2-hydroxyglutaric aciduria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

D2HGDH 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=0.0027270317).

BP6

Variant 2-241751260-G-A is Benign according to our data. Variant chr2-241751260-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
D2HGDH	NM_152783.5 link	c.1012G>A	p.Val338Ile	missense_variant	Exon 8 of 10	ENST00000321264.9	NP_689996.4	Q8N465-1B4E3K7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9 link	c.1012G>A	p.Val338Ile	missense_variant	Exon 8 of 10	1	NM_152783.5	ENSP00000315351.4		Q8N465-1

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

39048

AN:

152020

Hom.:

5160

Cov.:

show subpopulations

Gnomad AFR

AF:

0.289

Gnomad AMI

AF:

0.241

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.267

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.247

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.262

Gnomad OTH

AF:

0.252

GnomAD2 exomes

AF:

0.242

AC:

60864

AN:

251084

AF XY:

0.248

show subpopulations

Gnomad AFR exome

AF:

0.282

Gnomad AMR exome

AF:

0.175

Gnomad ASJ exome

AF:

0.268

Gnomad EAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.235

Gnomad NFE exome

AF:

0.268

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.254

AC:

370923

AN:

1461570

Hom.:

47987

Cov.:

AF XY:

0.254

AC XY:

185037

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.289

AC:

9667

AN:

33478

American (AMR)

AF:

0.177

AC:

7936

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

7125

AN:

26136

East Asian (EAS)

AF:

0.131

AC:

5213

AN:

39698

South Asian (SAS)

AF:

0.267

AC:

23057

AN:

86258

European-Finnish (FIN)

AF:

0.238

AC:

12691

AN:

53220

Middle Eastern (MID)

AF:

0.331

AC:

1906

AN:

5766

European-Non Finnish (NFE)

AF:

0.259

AC:

288188

AN:

1111912

Other (OTH)

AF:

0.251

AC:

15140

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

16321

32641

48962

65282

81603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9606

19212

28818

38424

48030

<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:

0.257

AC:

39075

AN:

152138

Hom.:

5167

Cov.:

AF XY:

0.255

AC XY:

18979

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.289

AC:

11986

AN:

41462

American (AMR)

AF:

0.199

AC:

3038

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

928

AN:

3472

East Asian (EAS)

AF:

0.123

AC:

638

AN:

5180

South Asian (SAS)

AF:

0.248

AC:

1194

AN:

4820

European-Finnish (FIN)

AF:

0.247

AC:

2615

AN:

10598

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.262

AC:

17842

AN:

67994

Other (OTH)

AF:

0.253

AC:

534

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1507

3014

4520

6027

7534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.260

Hom.:

17413

Bravo

AF:

0.252

TwinsUK

AF:

0.251

AC:

929

ALSPAC

AF:

0.242

AC:

933

ESP6500AA

AF:

0.281

AC:

1238

ESP6500EA

AF:

0.266

AC:

2282

ExAC

AF:

0.248

AC:

30111

Asia WGS

AF:

0.189

AC:

658

AN:

3478

EpiCase

AF:

0.271

EpiControl

AF:

0.277

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1

Benign:3

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:3

Feb 15, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

1.6

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.10

B;.;.

Vest4

0.044

MPC

0.32

ClinPred

0.0075

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.065

gMVP

0.32

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over