NM_152783.5:c.43C>G

Variant names:

• chr2-241735267-C-G
• rs4675887
• NM_152783.5:c.43C>G

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.43C>G​(p.Arg15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,518,798 control chromosomes in the GnomAD database, including 403 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R15R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0084 (51 hom., cov: 34)
  • Exomes 𝑓: 0.0058 (352 hom.)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.861
• Publications: 6 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=0.001637876).
• BP6: Variant 2-241735267-C-G is Benign according to our data. Variant chr2-241735267-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152783.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	NM_152783.5	MANE Select	c.43C>G	p.Arg15Gly	missense	Exon 2 of 10	NP_689996.4
	D2HGDH	NR_109778.2		n.201C>G		non_coding_transcript_exon	Exon 2 of 8
	D2HGDH	NM_001352824.2		c.-502C>G		5_prime_UTR	Exon 2 of 10	NP_001339753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.43C>G	p.Arg15Gly	missense	Exon 2 of 10	ENSP00000315351.4
	D2HGDH	ENST00000436747.5	TSL:1	n.43C>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000400212.1
	ENSG00000215692	ENST00000400768.2	TSL:4	n.232G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00840 AC: 1278 AN: 152148 Hom.: 49 Cov.: 34

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00952

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0294 AC: 3407 AN: 115976 AF XY: 0.0229

Gnomad AFR exome AF: 0.00378

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0480

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.00582 AC: 7957 AN: 1366538 Hom.: 352 Cov.: 29 AF XY: 0.00539 AC XY: 3636 AN XY: 674148

African (AFR) AF: 0.00137 AC: 40 AN: 29226

American (AMR) AF: 0.108 AC: 3649 AN: 33696

Ashkenazi Jewish (ASJ) AF: 0.0000417 AC: 1 AN: 23968

East Asian (EAS) AF: 0.0680 AC: 2346 AN: 34496

South Asian (SAS) AF: 0.00169 AC: 130 AN: 77004

European-Finnish (FIN) AF: 0.0125 AC: 428 AN: 34180

Middle Eastern (MID) AF: 0.000988 AC: 4 AN: 4048

European-Non Finnish (NFE) AF: 0.000896 AC: 961 AN: 1072964

Other (OTH) AF: 0.00699 AC: 398 AN: 56956

GnomAD4 genome AF: 0.00839 AC: 1278 AN: 152260 Hom.: 51 Cov.: 34 AF XY: 0.00936 AC XY: 697 AN XY: 74442

African (AFR) AF: 0.00262 AC: 109 AN: 41572

American (AMR) AF: 0.0458 AC: 700 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0509 AC: 263 AN: 5168

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.00952 AC: 101 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68010

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.0134

ExAC AF: 0.0105 AC: 1001

Asia WGS AF: 0.0250 AC: 87 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Nov 08, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 10, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

D-2-hydroxyglutaric aciduria 1 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.86
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.28
Sift	Benign	0.049	D
Sift4G	Uncertain	0.014	D
Polyphen		0.0	B
Vest4		0.14
MPC		0.51
ClinPred		0.0045	T
GERP RS		0.25
Varity_R		0.10
gMVP		0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4675887; hg19: chr2-242674682;