Genetic Variant GLUD2:p.Arg151Cys (chrX-121048135-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_012084.4(GLUD2):c.451C>T(p.Arg151Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 2 hem. )

Failed GnomAD Quality Control

Consequence

GLUD2
NM_012084.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74

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 Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUD2	NM_012084.4 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 1 of 1	ENST00000328078.3	NP_036216.2	P49448A0A140VK14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLUD2	ENST00000328078.3 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 1 of 1	6	NM_012084.4	ENSP00000327589.1		P49448

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

112246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34404

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000273

AC:

AN:

1098084

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363460

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000237

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

112246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34404

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.451C>T (p.R151C) alteration is located in exon 1 (coding exon 1) of the GLUD2 gene. This alteration results from a C to T substitution at nucleotide position 451, causing the arginine (R) at amino acid position 151 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.2

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.68

Sift

Uncertain

0.011

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.38

MutPred

0.95

Loss of MoRF binding (P = 0.0322);

MVP

0.88

MPC

1.9

ClinPred

1.0

GERP RS

-0.30

Varity_R

0.60

gMVP

0.99

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over