dbSNP rs9697983: GLUD2:p.Ser498Ala (chrX-121049176-T-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -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. 13/20 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

Publications

24 publications found

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:

ENSG00000286163 (HGNC:):

ENSG00000286163 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 29936.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012084.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD2	NM_012084.4	MANE Select	c.1492T>G	p.Ser498Ala	missense	Exon 1 of 1	NP_036216.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD2	ENST00000328078.3	TSL:6 MANE Select	c.1492T>G	p.Ser498Ala	missense	Exon 1 of 1	ENSP00000327589.1	P49448
	ENSG00000286163	ENST00000768679.1		n.61-2061T>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

3475

AN:

112156

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0266

AC:

4888

AN:

183495

AF XY:

0.0283

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 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

African (AFR)

AF:

0.0546

AC:

1440

AN:

26395

American (AMR)

AF:

0.0119

AC:

418

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

375

AN:

19385

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30206

South Asian (SAS)

AF:

0.0479

AC:

2595

AN:

54145

European-Finnish (FIN)

AF:

0.0367

AC:

1489

AN:

40532

Middle Eastern (MID)

AF:

0.0477

AC:

197

AN:

4129

European-Non Finnish (NFE)

AF:

0.0242

AC:

20380

AN:

842055

Other (OTH)

AF:

0.0286

AC:

1317

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1184

2369

3553

4738

5922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

788

1576

2364

3152

3940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0309

AC:

3471

AN:

112210

Hom.:

Cov.:

AF XY:

0.0300

AC XY:

1031

AN XY:

34398

show subpopulations

African (AFR)

AF:

0.0508

AC:

1570

AN:

30896

American (AMR)

AF:

0.0173

AC:

184

AN:

10618

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

2646

East Asian (EAS)

AF:

0.000280

AC:

AN:

3567

South Asian (SAS)

AF:

0.0371

AC:

AN:

2669

European-Finnish (FIN)

AF:

0.0343

AC:

210

AN:

6122

Middle Eastern (MID)

AF:

0.0507

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0242

AC:

1289

AN:

53269

Other (OTH)

AF:

0.0323

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

134

267

401

534

668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0278

Hom.:

2103

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Parkinson disease, late-onset (3)

GLUD2-related disorder (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.0

(source)

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

PhyloP100

0.63

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

Mutation Taster

=73/27

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over