rs149504235

chr2-241755966-G-Achr2-241755966-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_152783.5(D2HGDH):c.1258G>A(p.Ala420Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,604,926 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.441

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015416682).
• BP6: Variant 2-241755966-G-A is Benign according to our data. Variant chr2-241755966-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158409.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00233 (355/152292) while in subpopulation NFE AF= 0.00337 (229/68012). AF 95% confidence interval is 0.00301. There are 0 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
D2HGDH	NM_152783.5	c.1258G>A	p.Ala420Thr	missense_variant	9/10	ENST00000321264.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
D2HGDH	ENST00000321264.9	c.1258G>A	p.Ala420Thr	missense_variant	9/10	1	NM_152783.5	P1

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00220 AC: 545 AN: 248050 Hom.: 1 AF XY: 0.00229 AC XY: 308 AN XY: 134552

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00151

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00236

Gnomad FIN exome AF: 0.00237

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00302 AC: 4380 AN: 1452634 Hom.: 9 Cov.: 36 AF XY: 0.00296 AC XY: 2137 AN XY: 720814

Gnomad4 AFR exome AF: 0.000571

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00214

Gnomad4 FIN exome AF: 0.00234

Gnomad4 NFE exome AF: 0.00345

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.00204 AC XY: 152 AN XY: 74476

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00268 Hom.: 1

Bravo AF: 0.00236

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00218 AC: 264

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1 Uncertain:1 Benign:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2015	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

D2HGDH: BP4, BS2 -

D2HGDH-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2022

This variant is classified as likely 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	0.068
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	3.8
Dann	Benign	0.97
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.15
Sift	Benign	0.27	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0080	B;.
Vest4		0.16
MVP		0.74
MPC		0.37
ClinPred		0.0036	T
GERP RS		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.53

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: rs149504235; hg19: chr2-242695381; COSMIC: COSV58319312; COSMIC: COSV58319312;