14-50302999-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024884.3(L2HGDH):c.159C>T(p.Ile53Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,607,172 control chromosomes in the GnomAD database, including 261,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 25453 hom., cov: 33)

Exomes 𝑓: 0.57 ( 235695 hom. )

Consequence

L2HGDH
NM_024884.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.255

Publications

33 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 Gene-Disease associations (from GenCC):

L-2-hydroxyglutaric aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

L2HGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 14-50302999-G-A is Benign according to our data. Variant chr14-50302999-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.255 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L2HGDH	NM_024884.3 link	c.159C>T	p.Ile53Ile	synonymous_variant	Exon 2 of 10	ENST00000267436.9	NP_079160.1	Q9H9P8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9 link	c.159C>T	p.Ile53Ile	synonymous_variant	Exon 2 of 10	1	NM_024884.3	ENSP00000267436.4		Q9H9P8-1

Frequencies

GnomAD3 genomes

AF:

0.578

AC:

87816

AN:

151968

Hom.:

25406

Cov.:

show subpopulations

Gnomad AFR

AF:

0.615

Gnomad AMI

AF:

0.509

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.526

Gnomad EAS

AF:

0.657

Gnomad SAS

AF:

0.567

Gnomad FIN

AF:

0.584

Gnomad MID

AF:

0.595

Gnomad NFE

AF:

0.571

Gnomad OTH

AF:

0.567

GnomAD2 exomes

AF:

0.565

AC:

141964

AN:

251298

AF XY:

0.566

show subpopulations

Gnomad AFR exome

AF:

0.621

Gnomad AMR exome

AF:

0.479

Gnomad ASJ exome

AF:

0.514

Gnomad EAS exome

AF:

0.658

Gnomad FIN exome

AF:

0.582

Gnomad NFE exome

AF:

0.568

Gnomad OTH exome

AF:

0.554

GnomAD4 exome

AF:

0.568

AC:

826137

AN:

1455086

Hom.:

235695

Cov.:

AF XY:

0.567

AC XY:

410874

AN XY:

724312

show subpopulations

African (AFR)

AF:

0.619

AC:

20639

AN:

33330

American (AMR)

AF:

0.485

AC:

21689

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.513

AC:

13387

AN:

26088

East Asian (EAS)

AF:

0.642

AC:

25438

AN:

39640

South Asian (SAS)

AF:

0.573

AC:

49335

AN:

86148

European-Finnish (FIN)

AF:

0.583

AC:

31084

AN:

53306

Middle Eastern (MID)

AF:

0.505

AC:

2906

AN:

5758

European-Non Finnish (NFE)

AF:

0.567

AC:

627134

AN:

1105930

Other (OTH)

AF:

0.574

AC:

34525

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

16074

32148

48222

64296

80370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17430

34860

52290

69720

87150

<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:

0.578

AC:

87927

AN:

152086

Hom.:

25453

Cov.:

AF XY:

0.576

AC XY:

42794

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.615

AC:

25523

AN:

41472

American (AMR)

AF:

0.500

AC:

7642

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.526

AC:

1827

AN:

3472

East Asian (EAS)

AF:

0.657

AC:

3402

AN:

5176

South Asian (SAS)

AF:

0.567

AC:

2738

AN:

4826

European-Finnish (FIN)

AF:

0.584

AC:

6173

AN:

10562

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.571

AC:

38785

AN:

67982

Other (OTH)

AF:

0.567

AC:

1198

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1941

3882

5824

7765

9706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

750

1500

2250

3000

3750

<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.:

68365

Bravo

AF:

0.570

Asia WGS

AF:

0.581

AC:

2021

AN:

3478

EpiCase

AF:

0.560

EpiControl

AF:

0.563

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 20, 2017

Athena Diagnostics

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

L-2-hydroxyglutaric aciduria

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.2

(source)

DANN

Benign

0.74

PhyloP100

-0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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