rs141343442

Variant names:

• chr2-241751355-T-C
• rs141343442
• NM_152783.5:c.1107T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_152783.5(D2HGDH):​c.1107T>C​(p.Asp369Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0476 in 1,613,616 control chromosomes in the GnomAD database, including 2,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (176 hom., cov: 33)
  • Exomes 𝑓: 0.049 (2058 hom.)
• Consequence: D2HGDH NM_152783.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.46
• Publications: 10 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.048).
• BP6: Variant 2-241751355-T-C is Benign according to our data. Variant chr2-241751355-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0901 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.1107T>C	p.Asp369Asp	synonymous	Exon 8 of 10	NP_689996.4
	D2HGDH	NM_001287249.2		c.705T>C	p.Asp235Asp	synonymous	Exon 7 of 9	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.546T>C	p.Asp182Asp	synonymous	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.1107T>C	p.Asp369Asp	synonymous	Exon 8 of 10	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.*1423T>C		non_coding_transcript_exon	Exon 9 of 12	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000470343.5	TSL:1	n.588T>C		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5886 AN: 152178 Hom.: 174 Cov.: 33

Gnomad AFR AF: 0.00808

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.0971

Gnomad FIN AF: 0.0746

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0540 AC: 13532 AN: 250776 AF XY: 0.0571

Gnomad AFR exome AF: 0.00672

Gnomad AMR exome AF: 0.0669

Gnomad ASJ exome AF: 0.0622

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.0725

Gnomad NFE exome AF: 0.0485

Gnomad OTH exome AF: 0.0566

GnomAD4 exome AF: 0.0485 AC: 70898 AN: 1461320 Hom.: 2058 Cov.: 34 AF XY: 0.0498 AC XY: 36217 AN XY: 726990

African (AFR) AF: 0.00711 AC: 238 AN: 33480

American (AMR) AF: 0.0633 AC: 2829 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 1679 AN: 26132

East Asian (EAS) AF: 0.00128 AC: 51 AN: 39698

South Asian (SAS) AF: 0.100 AC: 8649 AN: 86250

European-Finnish (FIN) AF: 0.0701 AC: 3708 AN: 52928

Middle Eastern (MID) AF: 0.0531 AC: 306 AN: 5764

European-Non Finnish (NFE) AF: 0.0455 AC: 50630 AN: 1111978

Other (OTH) AF: 0.0465 AC: 2808 AN: 60386

GnomAD4 genome AF: 0.0387 AC: 5892 AN: 152296 Hom.: 176 Cov.: 33 AF XY: 0.0419 AC XY: 3119 AN XY: 74474

African (AFR) AF: 0.00806 AC: 335 AN: 41564

American (AMR) AF: 0.0532 AC: 814 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3470

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5184

South Asian (SAS) AF: 0.0974 AC: 470 AN: 4826

European-Finnish (FIN) AF: 0.0746 AC: 792 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3101 AN: 68022

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0444 Hom.: 75

Bravo AF: 0.0334

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.0456

EpiControl AF: 0.0467

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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.044
DANN	Benign	0.51
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs141343442; hg19: chr2-242690770; COSMIC: COSV100344691;