chr2-241751330-C-T

Variant names:

• chr2-241751330-C-T
• rs1105273
• NM_152783.5:c.1082C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152783.5(D2HGDH):​c.1082C>T​(p.Ala361Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,572 control chromosomes in the GnomAD database, including 16,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. A361A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (2862 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13964 hom.)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.179
• Publications: 24 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057843626).
• BP6: Variant 2-241751330-C-T is Benign according to our data. Variant chr2-241751330-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
D2HGDH	NM_152783.5	c.1082C>T	p.Ala361Val	missense_variant	Exon 8 of 10	ENST00000321264.9	NP_689996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9	c.1082C>T	p.Ala361Val	missense_variant	Exon 8 of 10	1	NM_152783.5	ENSP00000315351.4

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26909 AN: 152054 Hom.: 2858 Cov.: 33

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.162 AC: 40568 AN: 250886 AF XY: 0.151

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.320

Gnomad ASJ exome AF: 0.0924

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.127 AC: 186154 AN: 1461400 Hom.: 13964 Cov.: 36 AF XY: 0.125 AC XY: 91025 AN XY: 727000

African (AFR) AF: 0.278 AC: 9298 AN: 33478

American (AMR) AF: 0.322 AC: 14397 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0932 AC: 2435 AN: 26136

East Asian (EAS) AF: 0.238 AC: 9441 AN: 39700

South Asian (SAS) AF: 0.114 AC: 9810 AN: 86248

European-Finnish (FIN) AF: 0.144 AC: 7661 AN: 53036

Middle Eastern (MID) AF: 0.104 AC: 602 AN: 5764

European-Non Finnish (NFE) AF: 0.112 AC: 124132 AN: 1111962

Other (OTH) AF: 0.139 AC: 8378 AN: 60386

GnomAD4 genome AF: 0.177 AC: 26943 AN: 152172 Hom.: 2862 Cov.: 33 AF XY: 0.179 AC XY: 13309 AN XY: 74408

African (AFR) AF: 0.274 AC: 11383 AN: 41516

American (AMR) AF: 0.266 AC: 4071 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 276 AN: 3470

East Asian (EAS) AF: 0.214 AC: 1105 AN: 5164

South Asian (SAS) AF: 0.118 AC: 570 AN: 4826

European-Finnish (FIN) AF: 0.145 AC: 1534 AN: 10592

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7533 AN: 67994

Other (OTH) AF: 0.190 AC: 403 AN: 2116

Alfa AF: 0.133 Hom.: 3603

Bravo AF: 0.194

TwinsUK AF: 0.117 AC: 432

ALSPAC AF: 0.109 AC: 422

ESP6500AA AF: 0.265 AC: 1168

ESP6500EA AF: 0.106 AC: 912

ExAC AF: 0.155 AC: 18831

Asia WGS AF: 0.198 AC: 686 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

D-2-hydroxyglutaric aciduria 1 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.21
DANN	Benign	0.82
DEOGEN2	Benign	0.067	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N;.;.
PhyloP100		0.18
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.59	N;N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0070	B;.;.
Vest4		0.067
MPC		0.38
ClinPred		0.0020	T
GERP RS		-7.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.60
Mutation Taster		=93/7	polymorphism (auto)

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: rs1105273; hg19: chr2-242690745; COSMIC: COSV58320490; COSMIC: COSV58320490;