rs2275591

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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:

L2HGDH (HGNC:):

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 made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 158799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50312098-A-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
L2HGDH	NM_024884.3 linkuse as main transcript	c.53T>G	p.Leu18Arg	missense_variant	1/10	ENST00000267436.9	NP_079160.1	Q9H9P8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9 linkuse as main transcript	c.53T>G	p.Leu18Arg	missense_variant	1/10	1	NM_024884.3	ENSP00000267436.4		Q9H9P8-1

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

GnomAD3 exomes

AF:

0.566

AC:

130229

AN:

229978

Hom.:

36753

AF XY:

0.566

AC XY:

71366

AN XY:

125990

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 SAS exome

AF:

0.543

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

Gnomad4 AFR exome

AF:

0.553

Gnomad4 AMR exome

AF:

0.536

Gnomad4 ASJ exome

AF:

0.511

Gnomad4 EAS exome

AF:

0.603

Gnomad4 SAS exome

AF:

0.546

Gnomad4 FIN exome

AF:

0.595

Gnomad4 NFE exome

AF:

0.578

Gnomad4 OTH exome

AF:

0.573

GnomAD4 genome

AF:

0.572

AC:

87004

AN:

152118

Hom.:

24879

Cov.:

AF XY:

0.570

AC XY:

42402

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.559

Gnomad4 AMR

AF:

0.554

Gnomad4 ASJ

AF:

0.520

Gnomad4 EAS

AF:

0.621

Gnomad4 SAS

AF:

0.535

Gnomad4 FIN

AF:

0.596

Gnomad4 NFE

AF:

0.582

Gnomad4 OTH

AF:

0.570

Alfa

AF:

0.567

Hom.:

36696

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -

L-2-hydroxyglutaric aciduria

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

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

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.041

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;.;.

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.55

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