rs139321130

Variant names:

• chr2-241751311-G-A
• rs139321130
• NM_152783.5:c.1063G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152783.5(D2HGDH):​c.1063G>A​(p.Gly355Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,613,932 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. G355V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (15 hom., cov: 33)
  • Exomes 𝑓: 0.011 (142 hom.)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.39
• Publications: 12 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: Labcorp Genetics (formerly Invitae), G2P
• D-2-hydroxyglutaric aciduria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031147897).
• BP6: Variant 2-241751311-G-A is Benign according to our data. Variant chr2-241751311-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00903 (1375/152314) while in subpopulation NFE AF = 0.0123 (836/68032). AF 95% confidence interval is 0.0116. There are 15 homozygotes in GnomAd4. There are 735 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.1063G>A	p.Gly355Ser	missense	Exon 8 of 10	NP_689996.4
	D2HGDH	NM_001287249.2		c.661G>A	p.Gly221Ser	missense	Exon 7 of 9	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.502G>A	p.Gly168Ser	missense	Exon 8 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.1063G>A	p.Gly355Ser	missense	Exon 8 of 10	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.*1379G>A		non_coding_transcript_exon	Exon 9 of 12	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000470343.5	TSL:1	n.544G>A		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00904 AC: 1376 AN: 152196 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00939 AC: 2359 AN: 251174 AF XY: 0.00922

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.0115 AC: 16756 AN: 1461618 Hom.: 142 Cov.: 33 AF XY: 0.0113 AC XY: 8215 AN XY: 727114

African (AFR) AF: 0.00140 AC: 47 AN: 33480

American (AMR) AF: 0.00186 AC: 83 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00406 AC: 350 AN: 86256

European-Finnish (FIN) AF: 0.0345 AC: 1832 AN: 53168

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0125 AC: 13919 AN: 1112004

Other (OTH) AF: 0.00810 AC: 489 AN: 60386

GnomAD4 genome AF: 0.00903 AC: 1375 AN: 152314 Hom.: 15 Cov.: 33 AF XY: 0.00987 AC XY: 735 AN XY: 74476

African (AFR) AF: 0.00166 AC: 69 AN: 41564

American (AMR) AF: 0.00157 AC: 24 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.0369 AC: 392 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0123 AC: 836 AN: 68032

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00975 Hom.: 21

Bravo AF: 0.00614

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.00944 AC: 1146

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.00949

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	D-2-hydroxyglutaric aciduria 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.4
DANN	Benign	0.86
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.54	N
PhyloP100		1.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.17
Sift	Benign	0.28	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.85
MPC		0.37
ClinPred		0.00041	T
GERP RS		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.36
Mutation Taster		=97/3	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: rs139321130; hg19: chr2-242690726; COSMIC: COSV58320847; COSMIC: COSV58320847;