rs9697983

chrX-121049176-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 12/18 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.625

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]

ACMG classification

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	UniProt
GLUD2	NM_012084.4	c.1492T>G	p.Ser498Ala	missense_variant	1/1	ENST00000328078.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLUD2	ENST00000328078.3	c.1492T>G	p.Ser498Ala	missense_variant	1/1		NM_012084.4	P1

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 3475 AN: 112156 Hom.: 44 Cov.: 23 AF XY: 0.0301 AC XY: 1034 AN XY: 34334

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.: 60 AF XY: 0.0283 AC XY: 1922 AN XY: 67925

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.: 31 AF XY: 0.0269 AC XY: 9768 AN XY: 363497

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.: 43 Cov.: 23 AF XY: 0.0300 AC XY: 1031 AN XY: 34398

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: 82

ALSPAC AF: 0.0204 AC: 59

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:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Parkinson disease, late-onset Uncertain:1 Benign:1

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	- -

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 condition Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	7.0
Dann	Benign	0.24
DEOGEN2	Benign	0.069	T
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.31	N
MutationTaster	Benign	0.0069	P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.030	N
REVEL	Uncertain	0.32
Sift	Benign	0.83	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.51
ClinPred		0.0029	T
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

Other links and lift over

dbSNP: rs9697983; hg19: chrX-120183030;