rs775046649

Variant names:

• chr2-241743731-C-A
• rs775046649
• NM_152783.5:c.600C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-241743731-C-A
• chr2-241743731-C-G
• chr2-241743731-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_152783.5(D2HGDH):​c.600C>A​(p.Ile200Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,186 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. I200I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: D2HGDH NM_152783.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.87
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-241743731-C-A is Benign according to our data. Variant chr2-241743731-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1666864.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.

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.600C>A	p.Ile200Ile	synonymous	Exon 5 of 10	NP_689996.4
	D2HGDH	NM_001287249.2		c.198C>A	p.Ile66Ile	synonymous	Exon 4 of 9	NP_001274178.1
	D2HGDH	NM_001352824.2		c.39C>A	p.Ile13Ile	synonymous	Exon 5 of 10	NP_001339753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.600C>A	p.Ile200Ile	synonymous	Exon 5 of 10	ENSP00000315351.4
	D2HGDH	ENST00000436747.5	TSL:1	n.583C>A		non_coding_transcript_exon	Exon 5 of 12	ENSP00000400212.1
	D2HGDH	ENST00000951632.1		c.747C>A	p.Ile249Ile	synonymous	Exon 6 of 12	ENSP00000621691.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248704 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461186 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726820

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111804

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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	-0.44
CADD	Benign	0.17
DANN	Benign	0.85
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

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: rs775046649; hg19: chr2-242683146;