14-50283988-G-C

Position:

• chr14-50283988-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024884.3(L2HGDH):​c.586C>G​(p.Arg196Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L2HGDH	NM_024884.3	c.586C>G	p.Arg196Gly	missense_variant	5/10	ENST00000267436.9	NP_079160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9	c.586C>G	p.Arg196Gly	missense_variant	5/10	1	NM_024884.3	ENSP00000267436.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.95	.;L;L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.2	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.54	T;T;T;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.0030	B;B;B;.
Vest4		0.65
MutPred		0.65		Gain of catalytic residue at D194 (P = 2e-04);Gain of catalytic residue at D194 (P = 2e-04);Gain of catalytic residue at D194 (P = 2e-04);Gain of catalytic residue at D194 (P = 2e-04);
MVP		0.72
MPC		0.27
ClinPred		0.78	D
GERP RS		4.6
Varity_R		0.18
gMVP		0.73

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: rs368140834; hg19: chr14-50750706;