rs146578303

chr2-241755984-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 5.84

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]

ACMG classification

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 GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
D2HGDH	NM_152783.5	c.1276G>A	p.Ala426Thr	missense_variant	9/10	ENST00000321264.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
D2HGDH	ENST00000321264.9	c.1276G>A	p.Ala426Thr	missense_variant	9/10	1	NM_152783.5	P1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152192 Hom.: 6 Cov.: 33

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.: 13 AF XY: 0.00710 AC XY: 950 AN XY: 133748

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.: 66 Cov.: 36 AF XY: 0.00701 AC XY: 5048 AN XY: 719654

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.: 6 Cov.: 33 AF XY: 0.00747 AC XY: 556 AN XY: 74474

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.: 1

Bravo AF: 0.00387

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00757 AC: 65

ExAC AF: 0.00707 AC: 858

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00712

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	D2HGDH: BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 07, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	Invitae	Jan 18, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2015	- -
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). -

D2HGDH-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
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	T
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

Other links and lift over

dbSNP: rs146578303; hg19: chr2-242695399; COSMIC: COSV100344692; COSMIC: COSV100344692;