X-121047832-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_012084.4(GLUD2):​c.148C>T​(p.Arg50Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,207,912 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.000027 ( 0 hom. 9 hem. )

Consequence

GLUD2
NM_012084.4 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.06
Variant links:
Genes affected
GLUD2 (HGNC:4336): (glutamate dehydrogenase 2) The protein encoded by this gene is localized to the mitochondrion and acts as a homohexamer to recycle glutamate during neurotransmission. The encoded enzyme catalyzes the reversible oxidative deamination of glutamate to alpha-ketoglutarate. This gene is intronless.[provided by RefSeq, Jan 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10437468).
BS2
High Hemizygotes in GnomAd4 at 2 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GLUD2NM_012084.4 linkc.148C>T p.Arg50Trp missense_variant Exon 1 of 1 ENST00000328078.3 NP_036216.2 P49448A0A140VK14

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GLUD2ENST00000328078.3 linkc.148C>T p.Arg50Trp missense_variant Exon 1 of 1 6 NM_012084.4 ENSP00000327589.1 P49448

Frequencies

GnomAD3 genomes
AF:
0.0000535
AC:
6
AN:
112250
Hom.:
0
Cov.:
23
AF XY:
0.0000580
AC XY:
2
AN XY:
34510
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000366
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000942
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000280
AC:
5
AN:
178549
Hom.:
0
AF XY:
0.0000606
AC XY:
4
AN XY:
66025
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000526
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000509
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000274
AC:
30
AN:
1095662
Hom.:
0
Cov.:
32
AF XY:
0.0000248
AC XY:
9
AN XY:
362534
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000370
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000535
AC:
6
AN:
112250
Hom.:
0
Cov.:
23
AF XY:
0.0000580
AC XY:
2
AN XY:
34510
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000366
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000942
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 11, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.148C>T (p.R50W) alteration is located in exon 1 (coding exon 1) of the GLUD2 gene. This alteration results from a C to T substitution at nucleotide position 148, causing the arginine (R) at amino acid position 50 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
14
DANN
Benign
0.94
DEOGEN2
Benign
0.14
T
FATHMM_MKL
Benign
0.031
N
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.10
T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.48
N
REVEL
Uncertain
0.35
Sift
Benign
0.081
T
Sift4G
Benign
0.19
T
Polyphen
0.0
B
Vest4
0.11
MutPred
0.51
Loss of disorder (P = 0.0017);
MVP
0.98
MPC
0.75
ClinPred
0.047
T
GERP RS
-1.9
Varity_R
0.066
gMVP
0.71

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

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

Other links and lift over

dbSNP: rs774912140; hg19: chrX-120181686; API