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):

• 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

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

Selected	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
	D2HGDH	NM_001352824.2		c.834G>A	p.Thr278Thr	synonymous	Exon 10 of 10	NP_001339753.1

Ensembl Transcripts

Selected	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
	D2HGDH	ENST00000436747.5	TSL:1	n.*2631G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000400212.1
	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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 16, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

D2HGDH-related disorder Benign:1

Jun 30, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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;