rs2275591

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-50312098-A-C
• chr14-50312098-A-G
• chr14-50312098-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000267436.9(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. 15/21 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 ENST00000267436.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 158799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000267436.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	NM_024884.3	MANE Select	c.53T>G	p.Leu18Arg	missense	Exon 1 of 10	NP_079160.1
	L2HGDH	NM_001425212.1		c.53T>G	p.Leu18Arg	missense	Exon 1 of 11	NP_001412141.1
	L2HGDH	NM_001425213.1		c.-202T>G		5_prime_UTR	Exon 1 of 12	NP_001412142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.53T>G	p.Leu18Arg	missense	Exon 1 of 10	ENSP00000267436.4
	L2HGDH	ENST00000261699.8	TSL:1	c.53T>G	p.Leu18Arg	missense	Exon 1 of 10	ENSP00000261699.4
	L2HGDH	ENST00000555423.5	TSL:1	c.53T>G	p.Leu18Arg	missense	Exon 1 of 6	ENSP00000450494.1

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

GnomAD2 exomes AF: 0.566 AC: 130229 AN: 229978 AF XY: 0.566

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 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

African (AFR) AF: 0.553 AC: 18472 AN: 33374

American (AMR) AF: 0.536 AC: 23385 AN: 43658

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 13282 AN: 25988

East Asian (EAS) AF: 0.603 AC: 23772 AN: 39414

South Asian (SAS) AF: 0.546 AC: 46626 AN: 85360

European-Finnish (FIN) AF: 0.595 AC: 30264 AN: 50900

Middle Eastern (MID) AF: 0.519 AC: 2957 AN: 5696

European-Non Finnish (NFE) AF: 0.578 AC: 641104 AN: 1109086

Other (OTH) AF: 0.573 AC: 34441 AN: 60096

GnomAD4 genome AF: 0.572 AC: 87004 AN: 152118 Hom.: 24879 Cov.: 33 AF XY: 0.570 AC XY: 42402 AN XY: 74384

African (AFR) AF: 0.559 AC: 23210 AN: 41498

American (AMR) AF: 0.554 AC: 8463 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1803 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3209 AN: 5168

South Asian (SAS) AF: 0.535 AC: 2583 AN: 4828

European-Finnish (FIN) AF: 0.596 AC: 6317 AN: 10592

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39546 AN: 67964

Other (OTH) AF: 0.570 AC: 1202 AN: 2110

Alfa AF: 0.567 Hom.: 45028

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	L-2-hydroxyglutaric aciduria (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.027	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.19
Sift	Benign	0.69	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.30
ClinPred		0.0060	T
GERP RS		-2.2
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.55
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV55413053; COSMIC: COSV55413053;