rs1105273

Positions:

chr2-241751330-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152783.5(D2HGDH):c.1082C>T(p.Ala361Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,572 control chromosomes in the GnomAD database, including 16,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2862 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13964 hom. )

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.179

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=0.0057843626).

BP6

Variant 2-241751330-C-T is Benign according to our data. Variant chr2-241751330-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5 link	c.1082C>T	p.Ala361Val	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.1082C>T	p.Ala361Val	missense_variant	8/10	1	NM_152783.5	ENSP00000315351.4		Q8N465-1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26909

AN:

152054

Hom.:

2858

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.189

GnomAD3 exomes

AF:

0.162

AC:

40568

AN:

250886

Hom.:

4189

AF XY:

0.151

AC XY:

20450

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.286

Gnomad AMR exome

AF:

0.320

Gnomad ASJ exome

AF:

0.0924

Gnomad EAS exome

AF:

0.218

Gnomad SAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.109

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.127

AC:

186154

AN:

1461400

Hom.:

13964

Cov.:

AF XY:

0.125

AC XY:

91025

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.278

Gnomad4 AMR exome

AF:

0.322

Gnomad4 ASJ exome

AF:

0.0932

Gnomad4 EAS exome

AF:

0.238

Gnomad4 SAS exome

AF:

0.114

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.112

Gnomad4 OTH exome

AF:

0.139

GnomAD4 genome

AF:

0.177

AC:

26943

AN:

152172

Hom.:

2862

Cov.:

AF XY:

0.179

AC XY:

13309

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.274

Gnomad4 AMR

AF:

0.266

Gnomad4 ASJ

AF:

0.0795

Gnomad4 EAS

AF:

0.214

Gnomad4 SAS

AF:

0.118

Gnomad4 FIN

AF:

0.145

Gnomad4 NFE

AF:

0.111

Gnomad4 OTH

AF:

0.190

Alfa

AF:

0.122

Hom.:

1949

Bravo

AF:

0.194

TwinsUK

AF:

0.117

AC:

432

ALSPAC

AF:

0.109

AC:

422

ESP6500AA

AF:

0.265

AC:

1168

ESP6500EA

AF:

0.106

AC:

912

ExAC

AF:

0.155

AC:

18831

Asia WGS

AF:

0.198

AC:

686

AN:

3478

EpiCase

AF:

0.105

EpiControl

AF:

0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

D-2-hydroxyglutaric aciduria 1

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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

0.060

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

0.21

DANN

Benign

0.82

DEOGEN2

Benign

0.067

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.54

T;T;T

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

N;.;.

PrimateAI

Benign

0.39

PROVEAN

Benign

0.59

N;N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0070

B;.;.

Vest4

0.067

MPC

0.38

ClinPred

0.0020

GERP RS

-7.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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