Genetic Variant GLUD2:p.Arg32Gly (chrX-121047778-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_012084.4(GLUD2):c.94C>G(p.Arg32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,172,973 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 37 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R32R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000090 ( 0 hom. 33 hem. )

Consequence

GLUD2
NM_012084.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051935017).

BS2

High Hemizygotes in GnomAd4 at 4 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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>G	p.Arg32Gly	missense	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>G	p.Arg32Gly	missense	Exon 1 of 1	ENSP00000327589.1	P49448
ENSG00000286163	ENST00000768679.1		n.61-3459C>G		intron	N/A
ENSG00000300121	ENST00000769195.1		n.-17G>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

111795

Hom.:

Cov.:

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:

0.00398

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000238

AC:

AN:

126315

AF XY:

0.000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00285

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000895

AC:

AN:

1061129

Hom.:

Cov.:

AF XY:

0.0000959

AC XY:

AN XY:

344063

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25423

American (AMR)

AF:

0.00

AC:

AN:

30268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17603

East Asian (EAS)

AF:

0.00302

AC:

AN:

28768

South Asian (SAS)

AF:

0.0000200

AC:

AN:

49886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37493

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3095

European-Non Finnish (NFE)

AF:

0.00000364

AC:

AN:

824235

Other (OTH)

AF:

0.0000902

AC:

AN:

44358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000125

AC:

AN:

111844

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30942

American (AMR)

AF:

0.00

AC:

AN:

10744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00400

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:

0.00

AC:

AN:

52915

Other (OTH)

AF:

0.00

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000223

ExAC

AF:

0.000222

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

9.9

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.12

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.0

PhyloP100

-0.12

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.52

REVEL

Benign

0.22

Sift

Benign

0.36

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.11

MutPred

0.32

Loss of methylation at R32 (P = 0.0015)

MVP

0.96

MPC

0.79

ClinPred

0.024

GERP RS

-2.0

PromoterAI

-0.14

Neutral

(source)

Varity_R

0.074

gMVP

0.58

Mutation Taster

=97/3

polymorphism

(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

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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