14-50312098-A-G

Variant names:

• chr14-50312098-A-G
• rs2275591
• NM_024884.3:c.53T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024884.3(L2HGDH):​c.53T>C​(p.Leu18Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L18R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.90
• Publications: 48 publications found

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: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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.068139285).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024884.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	NM_024884.3	MANE Select	c.53T>C	p.Leu18Pro	missense	Exon 1 of 10	NP_079160.1	Q9H9P8-1
	L2HGDH	NM_001425212.1		c.53T>C	p.Leu18Pro	missense	Exon 1 of 11	NP_001412141.1	Q9H9P8-1
	L2HGDH	NM_001425213.1		c.-202T>C		5_prime_UTR	Exon 1 of 12	NP_001412142.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.53T>C	p.Leu18Pro	missense	Exon 1 of 10	ENSP00000267436.4	Q9H9P8-1
	L2HGDH	ENST00000261699.8	TSL:1	c.53T>C	p.Leu18Pro	missense	Exon 1 of 10	ENSP00000261699.4	C9JVN9
	L2HGDH	ENST00000555423.5	TSL:1	c.53T>C	p.Leu18Pro	missense	Exon 1 of 6	ENSP00000450494.1	G3V272

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.11
DANN	Benign	0.66
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.034	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.20
Sift	Benign	0.38	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.086
MutPred		0.49		Gain of catalytic residue at G22 (P = 0)
MVP		0.30
MPC		0.33
ClinPred		0.039	T
GERP RS		-2.2
PromoterAI		0.20	Neutral
Varity_R		0.10
gMVP		0.53
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2275591; hg19: chr14-50778816;