2-241744700-T-C

Variant names:

• chr2-241744700-T-C
• rs4234097
• NM_152783.5:c.685-9T>C

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.685-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,613,924 control chromosomes in the GnomAD database, including 182,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24824 hom., cov: 33)
  • Exomes 𝑓: 0.46 (157966 hom.)
• Consequence: D2HGDH NM_152783.5 intron
• Scores: Splicing: ADA: 0.00002322
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.16
• Publications: 14 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 (BayesDel_noAF=-0.86).
• BP6: Variant 2-241744700-T-C is Benign according to our data. Variant chr2-241744700-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	NM_152783.5	MANE Select	c.685-9T>C		intron	N/A	NP_689996.4
	D2HGDH	NM_001287249.2		c.283-9T>C		intron	N/A	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.124-9T>C		intron	N/A	NP_001339753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.685-9T>C		intron	N/A	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.668-9T>C		intron	N/A	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000951632.1		c.832-9T>C		intron	N/A	ENSP00000621691.1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83564 AN: 152050 Hom.: 24775 Cov.: 33

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.559

GnomAD2 exomes AF: 0.484 AC: 121610 AN: 251324 AF XY: 0.478

Gnomad AFR exome AF: 0.802

Gnomad AMR exome AF: 0.550

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.361

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.453

Gnomad OTH exome AF: 0.476

GnomAD4 exome AF: 0.460 AC: 672828 AN: 1461756 Hom.: 157966 Cov.: 58 AF XY: 0.459 AC XY: 333794 AN XY: 727184

African (AFR) AF: 0.803 AC: 26871 AN: 33474

American (AMR) AF: 0.557 AC: 24913 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 11562 AN: 26134

East Asian (EAS) AF: 0.381 AC: 15112 AN: 39698

South Asian (SAS) AF: 0.484 AC: 41779 AN: 86256

European-Finnish (FIN) AF: 0.427 AC: 22800 AN: 53406

Middle Eastern (MID) AF: 0.555 AC: 3192 AN: 5750

European-Non Finnish (NFE) AF: 0.448 AC: 497909 AN: 1111928

Other (OTH) AF: 0.475 AC: 28690 AN: 60390

GnomAD4 genome AF: 0.550 AC: 83680 AN: 152168 Hom.: 24824 Cov.: 33 AF XY: 0.546 AC XY: 40630 AN XY: 74386

African (AFR) AF: 0.791 AC: 32839 AN: 41510

American (AMR) AF: 0.550 AC: 8411 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1503 AN: 3470

East Asian (EAS) AF: 0.356 AC: 1848 AN: 5190

South Asian (SAS) AF: 0.465 AC: 2247 AN: 4828

European-Finnish (FIN) AF: 0.439 AC: 4648 AN: 10590

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.448 AC: 30466 AN: 67972

Other (OTH) AF: 0.561 AC: 1183 AN: 2110

Alfa AF: 0.491 Hom.: 9855

Bravo AF: 0.569

Asia WGS AF: 0.457 AC: 1589 AN: 3478

EpiCase AF: 0.461

EpiControl AF: 0.462

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.79
DANN	Benign	0.42
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.080		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: rs4234097; hg19: chr2-242684115; COSMIC: COSV58321153; COSMIC: COSV58321153;