Genetic Variant GLUD2:p.Arg32Arg (chrX-121047778-C-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012084.4(GLUD2):c.94C>A(p.Arg32Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,172,972 control chromosomes in the GnomAD database, including 47 homozygotes. There are 793 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 31 hom., 415 hem., cov: 23)

Exomes 𝑓: 0.0013 ( 16 hom. 378 hem. )

Consequence

GLUD2
NM_012084.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.116

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant X-121047778-C-A is Benign according to our data. Variant chrX-121047778-C-A is described in ClinVar as Benign. ClinVar VariationId is 777827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.116 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1458/111842) while in subpopulation AFR AF = 0.0448 (1387/30940). AF 95% confidence interval is 0.0429. There are 31 homozygotes in GnomAd4. There are 415 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 gene

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.94C>A	p.Arg32Arg	synonymous	Exon 1 of 1	NP_036216.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLUD2	ENST00000328078.3	TSL:6 MANE Select	c.94C>A	p.Arg32Arg	synonymous	Exon 1 of 1	ENSP00000327589.1	P49448
ENSG00000286163	ENST00000768679.1		n.61-3459C>A		intron	N/A
ENSG00000300121	ENST00000769195.1		n.-17G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1442

AN:

111793

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0444

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00531

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00858

GnomAD2 exomes

AF:

0.00390

AC:

493

AN:

126315

AF XY:

0.00315

show subpopulations

Gnomad AFR exome

AF:

0.0552

Gnomad AMR exome

AF:

0.00264

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000390

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00134

AC:

1420

AN:

1061130

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

378

AN XY:

344064

show subpopulations

African (AFR)

AF:

0.0465

AC:

1183

AN:

25423

American (AMR)

AF:

0.00264

AC:

AN:

30268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17603

East Asian (EAS)

AF:

0.00

AC:

AN:

28769

South Asian (SAS)

AF:

0.000160

AC:

AN:

49886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37493

Middle Eastern (MID)

AF:

0.00129

AC:

AN:

3095

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

824235

Other (OTH)

AF:

0.00307

AC:

136

AN:

44358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0130

AC:

1458

AN:

111842

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

415

AN XY:

34280

show subpopulations

African (AFR)

AF:

0.0448

AC:

1387

AN:

30940

American (AMR)

AF:

0.00531

AC:

AN:

10744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3504

South Asian (SAS)

AF:

0.00

AC:

AN:

2701

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52915

Other (OTH)

AF:

0.00846

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000486

Hom.:

Bravo

AF:

0.0152

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.3

(source)

DANN

Benign

0.67

PhyloP100

-0.12

PromoterAI

-0.20

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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