2-241735388-G-A

Position:

chr2-241735388-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.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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 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

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:

(HGNC:):

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=0.0021398067).

BP6

Variant 2-241735388-G-A is Benign according to our data. Variant chr2-241735388-G-A is described in ClinVar as [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5 linkuse as main transcript	c.164G>A	p.Arg55Gln	missense_variant	2/10	ENST00000321264.9	NP_689996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9 linkuse as main transcript	c.164G>A	p.Arg55Gln	missense_variant	2/10	1	NM_152783.5	ENSP00000315351	P1	Q8N465-1
	ENST00000400768.2 linkuse as main transcript	n.111C>T		non_coding_transcript_exon_variant	1/2	4

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

GnomAD3 exomes

AF:

0.278

AC:

55268

AN:

198738

Hom.:

7955

AF XY:

0.286

AC XY:

31319

AN XY:

109552

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 SAS exome

AF:

0.296

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

Gnomad4 AFR exome

AF:

0.198

Gnomad4 AMR exome

AF:

0.198

Gnomad4 ASJ exome

AF:

0.377

Gnomad4 EAS exome

AF:

0.162

Gnomad4 SAS exome

AF:

0.297

Gnomad4 FIN exome

AF:

0.294

Gnomad4 NFE exome

AF:

0.311

Gnomad4 OTH exome

AF:

0.295

GnomAD4 genome

AF:

0.273

AC:

41597

AN:

152262

Hom.:

6006

Cov.:

AF XY:

0.271

AC XY:

20205

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.229

Gnomad4 ASJ

AF:

0.382

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.298

Gnomad4 FIN

AF:

0.298

Gnomad4 NFE

AF:

0.320

Gnomad4 OTH

AF:

0.273

Alfa

AF:

0.313

Hom.:

7520

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

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	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
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	-	- -

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

0.062

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.2

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

MutationTaster

Benign

1.0

P;P;P;P

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

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

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