rs145731647

Variant names:

• chr2-241741010-A-G
• rs145731647
• NM_152783.5:c.293-23A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-241741010-A-G
• chr2-241741010-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PP5

The NM_152783.5(D2HGDH):​c.293-23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: D2HGDH NM_152783.5 intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.80
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-241741010-A-G is Pathogenic according to our data. Variant chr2-241741010-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1854.Status of the report is no_assertion_criteria_provided, 0 stars.

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.293-23A>G		intron	N/A	NP_689996.4
	D2HGDH	NM_001287249.2		c.-110-23A>G		intron	N/A	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.-252-23A>G		intron	N/A	NP_001339753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.293-23A>G		intron	N/A	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.293-23A>G		intron	N/A	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000951632.1		c.440-23A>G		intron	N/A	ENSP00000621691.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249638 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458674 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 725794

African (AFR) AF: 0.0000299 AC: 1 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109412

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	D-2-hydroxyglutaric aciduria 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.5
DANN	Benign	0.58
PhyloP100		1.8
La Branchor		0.96
BranchPoint Hunter		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=38/43	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.66		Position offset: 4
DS_AL_spliceai		0.34		Position offset: 23

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

Other links and lift over

dbSNP: rs145731647; hg19: chr2-242680425;