14-50247181-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_ModerateBP6BP7BS1

The NM_024884.3(L2HGDH):ā€‹c.1269A>Gā€‹(p.Ala423Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,614,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00028 ( 0 hom., cov: 33)
Exomes š‘“: 0.00016 ( 1 hom. )

Consequence

L2HGDH
NM_024884.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.705
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
Variant 14-50247181-T-C is Benign according to our data. Variant chr14-50247181-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211346.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
BP7
Synonymous conserved (PhyloP=0.705 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152306) while in subpopulation EAS AF= 0.00559 (29/5190). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
L2HGDHNM_024884.3 linkc.1269A>G p.Ala423Ala synonymous_variant Exon 10 of 10 ENST00000267436.9 NP_079160.1 Q9H9P8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
L2HGDHENST00000267436.9 linkc.1269A>G p.Ala423Ala synonymous_variant Exon 10 of 10 1 NM_024884.3 ENSP00000267436.4 Q9H9P8-1
L2HGDHENST00000261699.8 linkc.1197-9456A>G intron_variant Intron 9 of 9 1 ENSP00000261699.4 C9JVN9
L2HGDHENST00000421284.7 linkc.1269A>G p.Ala423Ala synonymous_variant Exon 10 of 11 2 ENSP00000405559.3 Q9H9P8-1

Frequencies

GnomAD3 genomes
AF:
0.000269
AC:
41
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00538
Gnomad SAS
AF:
0.00165
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000593
AC:
149
AN:
251228
Hom.:
1
AF XY:
0.000545
AC XY:
74
AN XY:
135798
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00652
Gnomad SAS exome
AF:
0.000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000979
GnomAD4 exome
AF:
0.000159
AC:
232
AN:
1461864
Hom.:
1
Cov.:
32
AF XY:
0.000157
AC XY:
114
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00202
Gnomad4 SAS exome
AF:
0.000997
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000324
Gnomad4 OTH exome
AF:
0.000447
GnomAD4 genome
AF:
0.000276
AC:
42
AN:
152306
Hom.:
0
Cov.:
33
AF XY:
0.000430
AC XY:
32
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00559
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000670
Hom.:
0
Bravo
AF:
0.000230
Asia WGS
AF:
0.00433
AC:
15
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2014
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

L-2-hydroxyglutaric aciduria Benign:1
Jan 16, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Mar 30, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.43
CADD
Benign
12
DANN
Benign
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369101323; hg19: chr14-50713899; API