rs77940364

Variant names:

• chr2-241735388-G-A
• rs77940364
• NM_152783.5:c.164G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-241735388-G-A
• chr2-241735388-G-C
• chr2-241735388-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:7
• Conservation: PhyloP100: -0.906
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• D-2-hydroxyglutaric aciduria 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• D-2-hydroxyglutaric aciduria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000215692 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
D2HGDH	NM_152783.5	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 10	ENST00000321264.9	NP_689996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 10	1	NM_152783.5	ENSP00000315351.4

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

GnomAD2 exomes AF: 0.278 AC: 55268 AN: 198738 AF XY: 0.286

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 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

African (AFR) AF: 0.198 AC: 6615 AN: 33342

American (AMR) AF: 0.198 AC: 7885 AN: 39842

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 9676 AN: 25646

East Asian (EAS) AF: 0.162 AC: 6302 AN: 38874

South Asian (SAS) AF: 0.297 AC: 24808 AN: 83654

European-Finnish (FIN) AF: 0.294 AC: 13884 AN: 47152

Middle Eastern (MID) AF: 0.346 AC: 1974 AN: 5704

European-Non Finnish (NFE) AF: 0.311 AC: 343221 AN: 1103526

Other (OTH) AF: 0.295 AC: 17559 AN: 59618

GnomAD4 genome AF: 0.273 AC: 41597 AN: 152262 Hom.: 6006 Cov.: 35 AF XY: 0.271 AC XY: 20205 AN XY: 74442

African (AFR) AF: 0.206 AC: 8578 AN: 41570

American (AMR) AF: 0.229 AC: 3499 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1327 AN: 3472

East Asian (EAS) AF: 0.151 AC: 781 AN: 5172

South Asian (SAS) AF: 0.298 AC: 1437 AN: 4826

European-Finnish (FIN) AF: 0.298 AC: 3163 AN: 10604

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21739 AN: 67992

Other (OTH) AF: 0.273 AC: 578 AN: 2116

Alfa AF: 0.307 Hom.: 11160

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

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1 Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 15, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		-0.91
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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