chr2-241741010-A-T

Position:

• chr2-241741010-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_152783.5(D2HGDH):​c.293-23A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,610,596 control chromosomes in the GnomAD database, including 242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.013 (16 hom., cov: 32)
  • Exomes 𝑓: 0.015 (226 hom.)
• Consequence: D2HGDH NM_152783.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.80

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-241741010-A-T is Benign according to our data. Variant chr2-241741010-A-T is described in ClinVar as [Benign]. Clinvar id is 158418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1917/152030) while in subpopulation NFE AF= 0.0186 (1268/67990). AF 95% confidence interval is 0.0178. There are 16 homozygotes in gnomad4. There are 954 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5	c.293-23A>T		intron_variant		ENST00000321264.9	NP_689996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9	c.293-23A>T		intron_variant		1	NM_152783.5	ENSP00000315351.4
D2HGDH	ENST00000436747.5	n.293-23A>T		intron_variant		1		ENSP00000400212.1
D2HGDH	ENST00000403782.5	c.-110-23A>T		intron_variant		2		ENSP00000384723.1
D2HGDH	ENST00000400769.6	n.293-23A>T		intron_variant		2		ENSP00000383580.2

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1918 AN: 151924 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.0140 AC: 3496 AN: 249638 Hom.: 39 AF XY: 0.0142 AC XY: 1921 AN XY: 135082

Gnomad AFR exome AF: 0.00267

Gnomad AMR exome AF: 0.00577

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.00476

Gnomad FIN exome AF: 0.0289

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0149 AC: 21688 AN: 1458566 Hom.: 226 Cov.: 29 AF XY: 0.0148 AC XY: 10720 AN XY: 725742

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00464

Gnomad4 FIN exome AF: 0.0314

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0126 AC: 1917 AN: 152030 Hom.: 16 Cov.: 32 AF XY: 0.0128 AC XY: 954 AN XY: 74308

Gnomad4 AFR AF: 0.00263

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.0283

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00437

Gnomad4 FIN AF: 0.0278

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.00855

Alfa AF: 0.0235 Hom.: 4

Bravo AF: 0.0105

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	D2HGDH: BS1, BS2 -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

- -

D-2-hydroxyglutaric aciduria 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

D2HGDH-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.8
DANN	Benign	0.73
La Branchor		0.96
BranchPoint Hunter		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145731647; hg19: chr2-242680425;