chr2-241755984-G-A

Position:

chr2-241755984-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152783.5(D2HGDH):c.1276G>A(p.Ala426Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00716 in 1,603,256 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 66 hom. )

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 5.84

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:

D2HGDH (HGNC:):

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=0.010284096).

BP6

Variant 2-241755984-G-A is Benign according to our data. Variant chr2-241755984-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-241755984-G-A is described in Lovd as [Pathogenic]. Variant chr2-241755984-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00609 (927/152310) while in subpopulation NFE AF= 0.00664 (452/68026). AF 95% confidence interval is 0.00614. There are 6 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5 linkuse as main transcript	c.1276G>A	p.Ala426Thr	missense_variant	9/10	ENST00000321264.9	NP_689996.4	Q8N465-1B4E3K7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9 linkuse as main transcript	c.1276G>A	p.Ala426Thr	missense_variant	9/10	1	NM_152783.5	ENSP00000315351.4		Q8N465-1

Frequencies

GnomAD3 genomes

AF:

0.00609

AC:

927

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0308

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00664

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00710

AC:

1749

AN:

246360

Hom.:

AF XY:

0.00710

AC XY:

950

AN XY:

133748

show subpopulations

Gnomad AFR exome

AF:

0.000873

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.00830

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00214

Gnomad FIN exome

AF:

0.0281

Gnomad NFE exome

AF:

0.00780

Gnomad OTH exome

AF:

0.00828

GnomAD4 exome

AF:

0.00727

AC:

10545

AN:

1450946

Hom.:

Cov.:

AF XY:

0.00701

AC XY:

5048

AN XY:

719654

show subpopulations

Gnomad4 AFR exome

AF:

0.000873

Gnomad4 AMR exome

AF:

0.00200

Gnomad4 ASJ exome

AF:

0.00828

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00226

Gnomad4 FIN exome

AF:

0.0264

Gnomad4 NFE exome

AF:

0.00742

Gnomad4 OTH exome

AF:

0.00743

GnomAD4 genome

AF:

0.00609

AC:

927

AN:

152310

Hom.:

Cov.:

AF XY:

0.00747

AC XY:

556

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0308

Gnomad4 NFE

AF:

0.00664

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00631

Hom.:

Bravo

AF:

0.00387

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00757

AC:

ExAC

AF:

0.00707

AC:

858

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00638

EpiControl

AF:

0.00712

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	D2HGDH: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 07, 2016	- -

D-2-hydroxyglutaric aciduria 1

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Jul 17, 2017	BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2015	- -

D2HGDH-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.0020

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;T

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.4

N;D

REVEL

Uncertain

0.61

Sift

Benign

0.17

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.41

B;.

Vest4

0.82

MVP

0.89

MPC

0.39

ClinPred

0.025

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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