chr2-241735267-C-G

Position:

chr2-241735267-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000321264.9(D2HGDH):c.43C>G(p.Arg15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,518,798 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. R15R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0084 ( 51 hom., cov: 34)

Exomes 𝑓: 0.0058 ( 352 hom. )

Consequence

D2HGDH
ENST00000321264.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.861

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001637876).

BP6

Variant 2-241735267-C-G is Benign according to our data. Variant chr2-241735267-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 158420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5 linkuse as main transcript	c.43C>G	p.Arg15Gly	missense_variant	2/10	ENST00000321264.9	NP_689996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9 linkuse as main transcript	c.43C>G	p.Arg15Gly	missense_variant	2/10	1	NM_152783.5	ENSP00000315351	P1	Q8N465-1
	ENST00000400768.2 linkuse as main transcript	n.232G>C		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes

AF:

0.00840

AC:

1278

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0458

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0507

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00952

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0294

AC:

3407

AN:

115976

Hom.:

212

AF XY:

0.0229

AC XY:

1479

AN XY:

64492

show subpopulations

Gnomad AFR exome

AF:

0.00378

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0480

Gnomad SAS exome

AF:

0.00169

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.00582

AC:

7957

AN:

1366538

Hom.:

352

Cov.:

AF XY:

0.00539

AC XY:

3636

AN XY:

674148

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.108

Gnomad4 ASJ exome

AF:

0.0000417

Gnomad4 EAS exome

AF:

0.0680

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.0125

Gnomad4 NFE exome

AF:

0.000896

Gnomad4 OTH exome

AF:

0.00699

GnomAD4 genome

AF:

0.00839

AC:

1278

AN:

152260

Hom.:

Cov.:

AF XY:

0.00936

AC XY:

697

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.0458

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0509

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00952

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.0134

ExAC

AF:

0.0105

AC:

1001

Asia WGS

AF:

0.0250

AC:

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 08, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

D-2-hydroxyglutaric aciduria 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.041

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.0

REVEL

Benign

0.28

Sift

Benign

0.049

Sift4G

Uncertain

0.014

Polyphen

0.0

Vest4

0.14

MPC

0.51

ClinPred

0.0045

GERP RS

0.25

Varity_R

0.10

gMVP

0.60

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over