rs2275591

chr14-50312098-A-Cchr14-50312098-A-Gchr14-50312098-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.90

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]

DMAC2L (HGNC:):

ACMG classification

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	UniProt
L2HGDH	NM_024884.3	c.53T>G	p.Leu18Arg	missense_variant	1/10	ENST00000267436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L2HGDH	ENST00000267436.9	c.53T>G	p.Leu18Arg	missense_variant	1/10	1	NM_024884.3	P1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86912 AN: 152000 Hom.: 24846 Cov.: 33

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

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.: 65 AF XY: 0.572 AC XY: 413666 AN XY: 722642

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.: 33 AF XY: 0.570 AC XY: 42402 AN XY: 74384

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	- -

L-2-hydroxyglutaric aciduria Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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	0.070
BayesDel_addAF	Benign	-0.53	T
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	N
LIST_S2	Benign	0.027	T;.;T;T;T
MetaRNN	Benign	0.000013	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Uncertain	0.64	T
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	T
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

Other links and lift over

dbSNP: rs2275591; hg19: chr14-50778816; COSMIC: COSV55413053; COSMIC: COSV55413053;