rs113626637

Positions:

• chr14-50312145-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000267436.9(L2HGDH):​c.6G>T​(p.Val2=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,610,192 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (32 hom.)
• Consequence: L2HGDH ENST00000267436.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.256

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 14-50312145-C-A is Benign according to our data. Variant chr14-50312145-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 211349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.256 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00304 (463/152338) while in subpopulation NFE AF= 0.00554 (377/68026). AF 95% confidence interval is 0.00508. There are 0 homozygotes in gnomad4. There are 208 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L2HGDH	NM_024884.3	c.6G>T	p.Val2=	synonymous_variant	1/10	ENST00000267436.9	NP_079160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9	c.6G>T	p.Val2=	synonymous_variant	1/10	1	NM_024884.3	ENSP00000267436	P1

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 463 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00554

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00274 AC: 659 AN: 240246 Hom.: 4 AF XY: 0.00268 AC XY: 352 AN XY: 131338

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.000938

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000298

Gnomad FIN exome AF: 0.000846

Gnomad NFE exome AF: 0.00506

Gnomad OTH exome AF: 0.00338

GnomAD4 exome AF: 0.00550 AC: 8012 AN: 1457854 Hom.: 32 Cov.: 33 AF XY: 0.00530 AC XY: 3843 AN XY: 725260

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.000921

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00688

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00304 AC: 463 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.00279 AC XY: 208 AN XY: 74492

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00554

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00432 Hom.: 1

Bravo AF: 0.00320

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	L2HGDH: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -

L-2-hydroxyglutaric aciduria Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 31, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.9
DANN	Benign	0.72

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: rs113626637; hg19: chr14-50778863;