chr2-241767711-A-G

Variant names:

• chr2-241767711-A-G
• rs113782371
• NM_152783.5:c.1308A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152783.5(D2HGDH):​c.1308A>G​(p.Gly436Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,612,660 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: D2HGDH NM_152783.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006608
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.419
• Publications: 2 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.086).
• BP6: Variant 2-241767711-A-G is Benign according to our data. Variant chr2-241767711-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.419 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00241 (367/151980) while in subpopulation AFR AF = 0.00855 (354/41394). AF 95% confidence interval is 0.00782. There are 3 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.1308A>G	p.Gly436Gly	splice_region synonymous	Exon 10 of 10	NP_689996.4
	D2HGDH	NM_001287249.2		c.906A>G	p.Gly302Gly	splice_region synonymous	Exon 9 of 9	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.747A>G	p.Gly249Gly	splice_region synonymous	Exon 10 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.1308A>G	p.Gly436Gly	splice_region synonymous	Exon 10 of 10	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.*2544A>G		splice_region non_coding_transcript_exon	Exon 12 of 12	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000468064.5	TSL:1	n.1198A>G		splice_region non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 151862 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00841

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000632 AC: 156 AN: 246868 AF XY: 0.000358

Gnomad AFR exome AF: 0.00840

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000228 AC: 333 AN: 1460680 Hom.: 0 Cov.: 34 AF XY: 0.000190 AC XY: 138 AN XY: 726686

African (AFR) AF: 0.00759 AC: 254 AN: 33466

American (AMR) AF: 0.000560 AC: 25 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111598

Other (OTH) AF: 0.000729 AC: 44 AN: 60350

GnomAD4 genome AF: 0.00241 AC: 367 AN: 151980 Hom.: 3 Cov.: 33 AF XY: 0.00225 AC XY: 167 AN XY: 74278

African (AFR) AF: 0.00855 AC: 354 AN: 41394

American (AMR) AF: 0.000523 AC: 8 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67928

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00136 Hom.: 3

Bravo AF: 0.00266

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	D-2-hydroxyglutaric aciduria 1 (2)
-	-	1	D2HGDH-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.2
DANN	Benign	0.51
PhyloP100		-0.42
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.012
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: rs113782371; hg19: chr2-242707126;