rs113626637

Variant names:

• chr14-50312145-C-A
• rs113626637
• NM_024884.3:c.6G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024884.3(L2HGDH):​c.6G>T​(p.Val2Val) 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 NM_024884.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.256
• Publications: 2 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 -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 32 AR gene

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.6G>T	p.Val2Val	synonymous	Exon 1 of 10	NP_079160.1	Q9H9P8-1
	L2HGDH	NM_001425212.1		c.6G>T	p.Val2Val	synonymous	Exon 1 of 11	NP_001412141.1	Q9H9P8-1
	L2HGDH	NM_001425213.1		c.-249G>T		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.6G>T	p.Val2Val	synonymous	Exon 1 of 10	ENSP00000267436.4	Q9H9P8-1
	L2HGDH	ENST00000261699.8	TSL:1	c.6G>T	p.Val2Val	synonymous	Exon 1 of 10	ENSP00000261699.4	C9JVN9
	L2HGDH	ENST00000555423.5	TSL:1	c.6G>T	p.Val2Val	synonymous	Exon 1 of 6	ENSP00000450494.1	G3V272

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

GnomAD2 exomes AF: 0.00274 AC: 659 AN: 240246 AF XY: 0.00268

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 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

African (AFR) AF: 0.000897 AC: 30 AN: 33430

American (AMR) AF: 0.000921 AC: 41 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26070

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39632

South Asian (SAS) AF: 0.000267 AC: 23 AN: 85982

European-Finnish (FIN) AF: 0.000805 AC: 41 AN: 50952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00688 AC: 7645 AN: 1111228

Other (OTH) AF: 0.00333 AC: 201 AN: 60280

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

African (AFR) AF: 0.00108 AC: 45 AN: 41572

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00554 AC: 377 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00469 Hom.: 1

Bravo AF: 0.00320

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	L-2-hydroxyglutaric aciduria (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.9
DANN	Benign	0.72
PhyloP100		-0.26
PromoterAI		-0.053	Neutral
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: rs113626637; hg19: chr14-50778863; COSMIC: COSV108023877; COSMIC: COSV108023877;