rs142473303

chr2-241742507-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_152783.5(D2HGDH):c.423C>T(p.Pro141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,614,066 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: D2HGDH NM_152783.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -5.03

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-241742507-C-T is Benign according to our data. Variant chr2-241742507-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158419.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}. Variant chr2-241742507-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00169 (258/152254) while in subpopulation NFE AF= 0.00288 (196/68014). AF 95% confidence interval is 0.00255. There are 1 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
D2HGDH	NM_152783.5	c.423C>T	p.Pro141=	synonymous_variant	4/10	ENST00000321264.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
D2HGDH	ENST00000321264.9	c.423C>T	p.Pro141=	synonymous_variant	4/10	1	NM_152783.5	P1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00180 AC: 452 AN: 250910 Hom.: 0 AF XY: 0.00180 AC XY: 244 AN XY: 135680

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00597

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00265 AC: 3878 AN: 1461812 Hom.: 8 Cov.: 32 AF XY: 0.00259 AC XY: 1886 AN XY: 727200

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00635

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00317

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74438

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.00156

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

D-2-hydroxyglutaric aciduria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 17, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.46
Dann	Benign	0.84
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: rs142473303; hg19: chr2-242681922;