rs77940364

chr2-241735388-G-Achr2-241735388-G-Cchr2-241735388-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (6006 hom., cov: 35)
  • Exomes 𝑓: 0.30 (66404 hom.)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.906

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]

(HGNC:):

ACMG classification

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	UniProt
D2HGDH	NM_152783.5	c.164G>A	p.Arg55Gln	missense_variant	2/10	ENST00000321264.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41593 AN: 152144 Hom.: 6005 Cov.: 35

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

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.: 43 AF XY: 0.302 AC XY: 215402 AN XY: 713498

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.: 35 AF XY: 0.271 AC XY: 20205 AN XY: 74442

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:6

Revision: criteria provided, multiple submitters, no conflicts

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	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	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -
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	0.062
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.2
Dann	Benign	0.97
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.86	N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.14
Sift	Benign	0.64	T
Sift4G	Benign	0.57	T
Polyphen		0.032	B
Vest4		0.032
MPC		0.43
ClinPred		0.0048	T
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

Other links and lift over

dbSNP: rs77940364; hg19: chr2-242674803; COSMIC: COSV58319692;