rs1106639

Positions:

chr2-241751260-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5 link	c.1012G>A	p.Val338Ile	missense_variant	8/10	ENST00000321264.9	NP_689996.4	Q8N465-1B4E3K7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9 link	c.1012G>A	p.Val338Ile	missense_variant	8/10	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

GnomAD3 exomes

AF:

0.242

AC:

60864

AN:

251084

Hom.:

7712

AF XY:

0.248

AC XY:

33625

AN XY:

135780

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 SAS exome

AF:

0.266

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

Gnomad4 AFR exome

AF:

0.289

Gnomad4 AMR exome

AF:

0.177

Gnomad4 ASJ exome

AF:

0.273

Gnomad4 EAS exome

AF:

0.131

Gnomad4 SAS exome

AF:

0.267

Gnomad4 FIN exome

AF:

0.238

Gnomad4 NFE exome

AF:

0.259

Gnomad4 OTH exome

AF:

0.251

GnomAD4 genome

AF:

0.257

AC:

39075

AN:

152138

Hom.:

5167

Cov.:

AF XY:

0.255

AC XY:

18979

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.289

Gnomad4 AMR

AF:

0.199

Gnomad4 ASJ

AF:

0.267

Gnomad4 EAS

AF:

0.123

Gnomad4 SAS

AF:

0.248

Gnomad4 FIN

AF:

0.247

Gnomad4 NFE

AF:

0.262

Gnomad4 OTH

AF:

0.253

Alfa

AF:

0.261

Hom.:

8356

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

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

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

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;.;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over