rs2297995

Variant names:

• chr14-50302999-G-A
• rs2297995
• NM_024884.3:c.159C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-50302999-G-A
• chr14-50302999-G-T

Variant summary

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

The NM_001425215.1(L2HGDH):​c.-467C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,607,172 control chromosomes in the GnomAD database, including 261,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25453 hom., cov: 33)
  • Exomes 𝑓: 0.57 (235695 hom.)
• Consequence: L2HGDH NM_001425215.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.255
• Publications: 33 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]

L2HGDH Gene-Disease associations (from GenCC):

• L-2-hydroxyglutaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-50302999-G-A is Benign according to our data. Variant chr14-50302999-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425215.1. 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.159C>T	p.Ile53Ile	synonymous	Exon 2 of 10	NP_079160.1
	L2HGDH	NM_001425215.1		c.-467C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	NP_001412144.1
	L2HGDH	NM_001425216.1		c.-388C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	NP_001412145.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.159C>T	p.Ile53Ile	synonymous	Exon 2 of 10	ENSP00000267436.4
	L2HGDH	ENST00000261699.8	TSL:1	c.159C>T	p.Ile53Ile	synonymous	Exon 2 of 10	ENSP00000261699.4
	L2HGDH	ENST00000555423.5	TSL:1	c.159C>T	p.Ile53Ile	synonymous	Exon 2 of 6	ENSP00000450494.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87816 AN: 151968 Hom.: 25406 Cov.: 33

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.567

GnomAD2 exomes AF: 0.565 AC: 141964 AN: 251298 AF XY: 0.566

Gnomad AFR exome AF: 0.621

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.514

Gnomad EAS exome AF: 0.658

Gnomad FIN exome AF: 0.582

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.568 AC: 826137 AN: 1455086 Hom.: 235695 Cov.: 32 AF XY: 0.567 AC XY: 410874 AN XY: 724312

African (AFR) AF: 0.619 AC: 20639 AN: 33330

American (AMR) AF: 0.485 AC: 21689 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 13387 AN: 26088

East Asian (EAS) AF: 0.642 AC: 25438 AN: 39640

South Asian (SAS) AF: 0.573 AC: 49335 AN: 86148

European-Finnish (FIN) AF: 0.583 AC: 31084 AN: 53306

Middle Eastern (MID) AF: 0.505 AC: 2906 AN: 5758

European-Non Finnish (NFE) AF: 0.567 AC: 627134 AN: 1105930

Other (OTH) AF: 0.574 AC: 34525 AN: 60174

GnomAD4 genome AF: 0.578 AC: 87927 AN: 152086 Hom.: 25453 Cov.: 33 AF XY: 0.576 AC XY: 42794 AN XY: 74348

African (AFR) AF: 0.615 AC: 25523 AN: 41472

American (AMR) AF: 0.500 AC: 7642 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1827 AN: 3472

East Asian (EAS) AF: 0.657 AC: 3402 AN: 5176

South Asian (SAS) AF: 0.567 AC: 2738 AN: 4826

European-Finnish (FIN) AF: 0.584 AC: 6173 AN: 10562

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38785 AN: 67982

Other (OTH) AF: 0.567 AC: 1198 AN: 2112

Alfa AF: 0.567 Hom.: 68365

Bravo AF: 0.570

Asia WGS AF: 0.581 AC: 2021 AN: 3478

EpiCase AF: 0.560

EpiControl AF: 0.563

ClinVar

ClinVar submissions as Germline

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.2
DANN	Benign	0.74
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs2297995; hg19: chr14-50769717; COSMIC: COSV55558332; COSMIC: COSV55558332;