2-241741010-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.80

Publications

3 publications found

Variant links:

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

D2HGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
D2HGDH	NM_152783.5	MANE Select	c.293-23A>T	intron	N/A	NP_689996.4
D2HGDH	NM_001287249.2		c.-110-23A>T	intron	N/A	NP_001274178.1	B5MCV2
D2HGDH	NM_001352824.2		c.-252-23A>T	intron	N/A	NP_001339753.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1918

AN:

151924

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0140

AC:

3496

AN:

249638

AF XY:

0.0142

show subpopulations

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 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.:

AF XY:

0.0148

AC XY:

10720

AN XY:

725742

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33394

American (AMR)

AF:

0.00569

AC:

254

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

811

AN:

26112

East Asian (EAS)

AF:

0.000151

AC:

AN:

39682

South Asian (SAS)

AF:

0.00464

AC:

399

AN:

86078

European-Finnish (FIN)

AF:

0.0314

AC:

1673

AN:

53258

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0158

AC:

17500

AN:

1109320

Other (OTH)

AF:

0.0141

AC:

851

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1027

2054

3081

4108

5135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

598

1196

1794

2392

2990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0126

AC:

1917

AN:

152030

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

954

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00263

AC:

109

AN:

41454

American (AMR)

AF:

0.00687

AC:

105

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0283

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00437

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0278

AC:

293

AN:

10548

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0186

AC:

1268

AN:

67990

Other (OTH)

AF:

0.00855

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

190

285

380

475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0235

Hom.:

Bravo

AF:

0.0105

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

D-2-hydroxyglutaric aciduria 1 (1)

D2HGDH-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.8

(source)

DANN

Benign

0.73

PhyloP100

1.8

La Branchor

0.96

BranchPoint Hunter

6.0

Mutation Taster

=38/43

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over