rs111670322

Variant names:

• chr2-241767798-G-A
• rs111670322
• NM_152783.5:c.1395G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-241767798-G-A
• chr2-241767798-G-C
• chr2-241767798-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152783.5(D2HGDH):​c.1395G>A​(p.Thr465Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,612,206 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (162 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (166 hom.)
• Consequence: D2HGDH NM_152783.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.24
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.013).
• BP6: Variant 2-241767798-G-A is Benign according to our data. Variant chr2-241767798-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0857 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.1395G>A	p.Thr465Thr	synonymous	Exon 10 of 10	NP_689996.4
	D2HGDH	NM_001287249.2		c.993G>A	p.Thr331Thr	synonymous	Exon 9 of 9	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.834G>A	p.Thr278Thr	synonymous	Exon 10 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.1395G>A	p.Thr465Thr	synonymous	Exon 10 of 10	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.*2631G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000468064.5	TSL:1	n.1285G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3844 AN: 152088 Hom.: 160 Cov.: 33

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00647 AC: 1581 AN: 244238 AF XY: 0.00464

Gnomad AFR exome AF: 0.0900

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00262 AC: 3826 AN: 1460000 Hom.: 166 Cov.: 34 AF XY: 0.00229 AC XY: 1662 AN XY: 726300

African (AFR) AF: 0.0927 AC: 3104 AN: 33468

American (AMR) AF: 0.00450 AC: 201 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86216

European-Finnish (FIN) AF: 0.0000382 AC: 2 AN: 52388

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5758

European-Non Finnish (NFE) AF: 0.000118 AC: 131 AN: 1111460

Other (OTH) AF: 0.00562 AC: 339 AN: 60334

GnomAD4 genome AF: 0.0254 AC: 3866 AN: 152206 Hom.: 162 Cov.: 33 AF XY: 0.0251 AC XY: 1865 AN XY: 74428

African (AFR) AF: 0.0881 AC: 3655 AN: 41498

American (AMR) AF: 0.0103 AC: 157 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67986

Other (OTH) AF: 0.0171 AC: 36 AN: 2110

Alfa AF: 0.00921 Hom.: 18

Bravo AF: 0.0281

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.15
DANN	Benign	0.76
PhyloP100		-1.2
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: rs111670322; hg19: chr2-242707213;