rs9697983

Positions:

chrX-121049176-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_012084.4(GLUD2):c.1492T>G(p.Ser498Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,210,351 control chromosomes in the GnomAD database, including 346 homozygotes. There are 10,799 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.031 ( 43 hom., 1031 hem., cov: 23)

Exomes 𝑓: 0.026 ( 303 hom. 9768 hem. )

Consequence

GLUD2
NM_012084.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.625

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]

GLUD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026293725).

BP6

Variant X-121049176-T-G is Benign according to our data. Variant chrX-121049176-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 29936.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLUD2	NM_012084.4 linkuse as main transcript	c.1492T>G	p.Ser498Ala	missense_variant	1/1	ENST00000328078.3	NP_036216.2	P49448A0A140VK14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLUD2	ENST00000328078.3 linkuse as main transcript	c.1492T>G	p.Ser498Ala	missense_variant	1/1	6	NM_012084.4	ENSP00000327589.1		P49448

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

3475

AN:

112156

Hom.:

Cov.:

AF XY:

0.0301

AC XY:

1034

AN XY:

34334

show subpopulations

Gnomad AFR

AF:

0.0510

Gnomad AMI

AF:

0.0102

Gnomad AMR

AF:

0.0174

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.0370

Gnomad FIN

AF:

0.0343

Gnomad MID

AF:

0.0544

Gnomad NFE

AF:

0.0242

Gnomad OTH

AF:

0.0327

GnomAD3 exomes

AF:

0.0266

AC:

4888

AN:

183495

Hom.:

AF XY:

0.0283

AC XY:

1922

AN XY:

67925

show subpopulations

Gnomad AFR exome

AF:

0.0498

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.0000721

Gnomad SAS exome

AF:

0.0480

Gnomad FIN exome

AF:

0.0364

Gnomad NFE exome

AF:

0.0264

Gnomad OTH exome

AF:

0.0262

GnomAD4 exome

AF:

0.0257

AC:

28212

AN:

1098141

Hom.:

303

Cov.:

AF XY:

0.0269

AC XY:

9768

AN XY:

363497

show subpopulations

Gnomad4 AFR exome

AF:

0.0546

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0479

Gnomad4 FIN exome

AF:

0.0367

Gnomad4 NFE exome

AF:

0.0242

Gnomad4 OTH exome

AF:

0.0286

GnomAD4 genome

AF:

0.0309

AC:

3471

AN:

112210

Hom.:

Cov.:

AF XY:

0.0300

AC XY:

1031

AN XY:

34398

show subpopulations

Gnomad4 AFR

AF:

0.0508

Gnomad4 AMR

AF:

0.0173

Gnomad4 ASJ

AF:

0.0193

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.0371

Gnomad4 FIN

AF:

0.0343

Gnomad4 NFE

AF:

0.0242

Gnomad4 OTH

AF:

0.0323

Alfa

AF:

0.0268

Hom.:

1661

Bravo

AF:

0.0297

TwinsUK

AF:

0.0221

AC:

ALSPAC

AF:

0.0204

AC:

ESP6500AA

AF:

0.0542

AC:

208

ESP6500EA

AF:

0.0271

AC:

182

ExAC

AF:

0.0284

AC:

3447

EpiCase

AF:

0.0300

EpiControl

AF:

0.0288

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Parkinson disease, late-onset

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The GLUD2 c.1492T>G variant has been reported previously to be a modifier of age of onset in Parkinsonism patient (Plaitakis A et al). The variant has been submitted to ClinVar as Pathogenic based on the same publication. Experimental studies have shown that estrogen hormones inhibited the enhanced basal activity of the X-linked variant much more powerfully than that of the widely expressed hGDH1. Hence, it seems likely that, in females, estrogens may nullify the gain-of-function effects observed in male patients by blocking the overactive variant enzyme from metabolizing increased amounts of glutamate (and, in the process, damaging nigral cells). Understanding the mechanisms by which the variant hastens the commencement of PD symptoms could provide a means for retarding the development of this disorder (Plaitakis A et al). This variant is reported in gnomAD database at a frequency of 2.756% with 2188 number of hemizygotes. The allele frequency is however expected to be skewed in gnomAD. The amino acid Ser at position 498 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ser498Ala in GLUD2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Considering the relative high frequency of the variant in the gnomAD, this variant has been classified as Uncertain significance. -
Benign, no assertion criteria provided	literature only	OMIM	Mar 01, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 05, 2020

ACMG classification criteria: BP4 -

GLUD2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.0

DANN

Benign

0.24

DEOGEN2

Benign

0.069

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.82

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.60

MutationAssessor

Benign

-0.31

PrimateAI

Benign

0.47

PROVEAN

Benign

0.030

REVEL

Uncertain

0.32

Sift

Benign

0.83

Sift4G

Benign

0.93

Polyphen

0.0

Vest4

0.023

MPC

0.51

ClinPred

0.0029

GERP RS

0.71

Varity_R

0.089

gMVP

0.51

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over