rs144668507

chr2-241751314-C-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.1066C>T(p.His356Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,946 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (57 hom.)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.711

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=0.00381127).
• BP6: Variant 2-241751314-C-T is Benign according to our data. Variant chr2-241751314-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
D2HGDH	NM_152783.5	c.1066C>T	p.His356Tyr	missense_variant	8/10	ENST00000321264.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
D2HGDH	ENST00000321264.9	c.1066C>T	p.His356Tyr	missense_variant	8/10	1	NM_152783.5	P1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2530 AN: 152208 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00409 AC: 1028 AN: 251188 Hom.: 23 AF XY: 0.00289 AC XY: 393 AN XY: 135864

Gnomad AFR exome AF: 0.0569

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00166 AC: 2424 AN: 1461620 Hom.: 57 Cov.: 33 AF XY: 0.00136 AC XY: 990 AN XY: 727112

Gnomad4 AFR exome AF: 0.0617

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.0167 AC: 2539 AN: 152326 Hom.: 72 Cov.: 33 AF XY: 0.0155 AC XY: 1155 AN XY: 74488

Gnomad4 AFR AF: 0.0573

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00522 Hom.: 7

Bravo AF: 0.0185

ESP6500AA AF: 0.0601 AC: 265

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00508 AC: 617

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1 Benign:2

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	Jan 24, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	0.017
Dann	Benign	0.90
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.030	N
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.037	D;D;D
Polyphen		0.0020	B;.;.
Vest4		0.29
MVP		0.54
MPC		0.43
ClinPred		0.0054	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs144668507; hg19: chr2-242690729; COSMIC: COSV104414943; COSMIC: COSV104414943;