rs141343442

Positions:

• chr2-241751355-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152783.5(D2HGDH):​c.1107T>C​(p.Asp369=) 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

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-241751355-T-C is Benign according to our data. Variant chr2-241751355-T-C is described in ClinVar as [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5	c.1107T>C	p.Asp369=	synonymous_variant	8/10	ENST00000321264.9	NP_689996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9	c.1107T>C	p.Asp369=	synonymous_variant	8/10	1	NM_152783.5	ENSP00000315351	P1

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

GnomAD3 exomes AF: 0.0540 AC: 13532 AN: 250776 Hom.: 477 AF XY: 0.0571 AC XY: 7756 AN XY: 135750

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 SAS exome AF: 0.0991

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

Gnomad4 AFR exome AF: 0.00711

Gnomad4 AMR exome AF: 0.0633

Gnomad4 ASJ exome AF: 0.0643

Gnomad4 EAS exome AF: 0.00128

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.0701

Gnomad4 NFE exome AF: 0.0455

Gnomad4 OTH exome AF: 0.0465

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

Gnomad4 AFR AF: 0.00806

Gnomad4 AMR AF: 0.0532

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.0974

Gnomad4 FIN AF: 0.0746

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.0350

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

D-2-hydroxyglutaric aciduria 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.044
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

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