rs2275591

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024884.3(L2HGDH):c.53T>G(p.Leu18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 1,605,690 control chromosomes in the GnomAD database, including 264,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 24879 hom., cov: 33)

Exomes 𝑓: 0.57 ( 239812 hom. )

Consequence

L2HGDH
NM_024884.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.90

Publications

48 publications found

Variant links:

Genes affected

L2HGDH (HGNC:20499): (L-2-hydroxyglutarate dehydrogenase) This gene encodes L-2-hydroxyglutarate dehydrogenase, a FAD-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe cognitive disability. [provided by RefSeq, Jul 2008]

L2HGDH links:

DMAC2L (HGNC:18799): (distal membrane arm assembly component 2 like) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. This gene encodes the subunit s, also known as factor B, of the proton channel. This subunit is necessary for the energy transduction activity of the ATP synthase complexes. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

DMAC2L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3381955E-5).

BP6

Variant 14-50312098-A-C is Benign according to our data. Variant chr14-50312098-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L2HGDH	NM_024884.3 link	c.53T>G	p.Leu18Arg	missense_variant	Exon 1 of 10	ENST00000267436.9	NP_079160.1	Q9H9P8-1
DMAC2L	NM_001382507.1 link	c.-333A>C		upstream_gene_variant		ENST00000557421.7	NP_001369436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9 link	c.53T>G	p.Leu18Arg	missense_variant	Exon 1 of 10	1	NM_024884.3	ENSP00000267436.4		Q9H9P8-1
DMAC2L	ENST00000557421.7 link	c.-333A>C		upstream_gene_variant		5	NM_001382507.1	ENSP00000506374.1		A0A5K1VW60

Frequencies

GnomAD3 genomes

AF:

0.572

AC:

86912

AN:

152000

Hom.:

24846

Cov.:

show subpopulations

Gnomad AFR

AF:

0.559

Gnomad AMI

AF:

0.531

Gnomad AMR

AF:

0.553

Gnomad ASJ

AF:

0.520

Gnomad EAS

AF:

0.620

Gnomad SAS

AF:

0.535

Gnomad FIN

AF:

0.596

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.582

Gnomad OTH

AF:

0.569

GnomAD2 exomes

AF:

0.566

AC:

130229

AN:

229978

AF XY:

0.566

show subpopulations

Gnomad AFR exome

AF:

0.560

Gnomad AMR exome

AF:

0.531

Gnomad ASJ exome

AF:

0.511

Gnomad EAS exome

AF:

0.613

Gnomad FIN exome

AF:

0.595

Gnomad NFE exome

AF:

0.578

Gnomad OTH exome

AF:

0.556

GnomAD4 exome

AF:

0.574

AC:

834303

AN:

1453572

Hom.:

239812

Cov.:

AF XY:

0.572

AC XY:

413666

AN XY:

722642

show subpopulations

African (AFR)

AF:

0.553

AC:

18472

AN:

33374

American (AMR)

AF:

0.536

AC:

23385

AN:

43658

Ashkenazi Jewish (ASJ)

AF:

0.511

AC:

13282

AN:

25988

East Asian (EAS)

AF:

0.603

AC:

23772

AN:

39414

South Asian (SAS)

AF:

0.546

AC:

46626

AN:

85360

European-Finnish (FIN)

AF:

0.595

AC:

30264

AN:

50900

Middle Eastern (MID)

AF:

0.519

AC:

2957

AN:

5696

European-Non Finnish (NFE)

AF:

0.578

AC:

641104

AN:

1109086

Other (OTH)

AF:

0.573

AC:

34441

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

22123

44245

66368

88490

110613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17726

35452

53178

70904

88630

<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:

0.572

AC:

87004

AN:

152118

Hom.:

24879

Cov.:

AF XY:

0.570

AC XY:

42402

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.559

AC:

23210

AN:

41498

American (AMR)

AF:

0.554

AC:

8463

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.520

AC:

1803

AN:

3470

East Asian (EAS)

AF:

0.621

AC:

3209

AN:

5168

South Asian (SAS)

AF:

0.535

AC:

2583

AN:

4828

European-Finnish (FIN)

AF:

0.596

AC:

6317

AN:

10592

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.582

AC:

39546

AN:

67964

Other (OTH)

AF:

0.570

AC:

1202

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

2014

4028

6043

8057

10071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

744

1488

2232

2976

3720

<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:

0.567

Hom.:

45028

Bravo

AF:

0.565

TwinsUK

AF:

0.591

AC:

2193

ALSPAC

AF:

0.570

AC:

2197

ESP6500AA

AF:

0.563

AC:

2465

ESP6500EA

AF:

0.563

AC:

4826

ExAC

AF:

0.555

AC:

66690

Asia WGS

AF:

0.541

AC:

1882

AN:

3478

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 17, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

L-2-hydroxyglutaric aciduria

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.041

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.0099

T;T;T;.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.027

T;.;T;T;T

MetaRNN

Benign

0.000013

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N;.;.

PhyloP100

-4.9

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.21

N;N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.69

T;T;T;T;T

Sift4G

Benign

0.47

T;T;T;T;T

Polyphen

0.0

B;B;B;.;.

Vest4

0.11

MPC

0.30

ClinPred

0.0060

GERP RS

-2.2

PromoterAI

0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.55

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over