rs149504235

Variant names:

• chr2-241755966-G-A
• rs149504235
• NM_152783.5:c.1258G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-241755966-G-A
• chr2-241755966-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

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. 15/21 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
• Publications: 9 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):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

ENSG00000234793 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_152783.5
• 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 VariationId is 158409.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	NM_152783.5	MANE Select	c.1258G>A	p.Ala420Thr	missense	Exon 9 of 10	NP_689996.4
	D2HGDH	NM_001287249.2		c.856G>A	p.Ala286Thr	missense	Exon 8 of 9	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.697G>A	p.Ala233Thr	missense	Exon 9 of 10	NP_001339753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.1258G>A	p.Ala420Thr	missense	Exon 9 of 10	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.*2494G>A		non_coding_transcript_exon	Exon 11 of 12	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000468064.5	TSL:1	n.1148G>A		non_coding_transcript_exon	Exon 2 of 3

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

GnomAD2 exomes AF: 0.00220 AC: 545 AN: 248050 AF XY: 0.00229

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 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

African (AFR) AF: 0.000571 AC: 19 AN: 33270

American (AMR) AF: 0.00146 AC: 65 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 39 AN: 26040

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39398

South Asian (SAS) AF: 0.00214 AC: 184 AN: 86094

European-Finnish (FIN) AF: 0.00234 AC: 122 AN: 52230

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.00345 AC: 3810 AN: 1105474

Other (OTH) AF: 0.00224 AC: 134 AN: 59884

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

African (AFR) AF: 0.000770 AC: 32 AN: 41564

American (AMR) AF: 0.00320 AC: 49 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00337 AC: 229 AN: 68012

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00261 Hom.: 3

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	D-2-hydroxyglutaric aciduria 1 (3)
-	-	1	D2HGDH-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.44
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.15
Sift	Benign	0.27	T
Sift4G	Benign	0.30	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
Mutation Taster		=99/1	polymorphism

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