Genetic Variant GLS2:p.Val353Met (chr12-56474711-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_013267.4(GLS2):c.1057G>A(p.Val353Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V353L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GLS2
NM_013267.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.96

Publications

0 publications found

Variant links:

Genes affected

GLS2 (HGNC:29570): (glutaminase 2) The protein encoded by this gene is a mitochondrial phosphate-activated glutaminase that catalyzes the hydrolysis of glutamine to stoichiometric amounts of glutamate and ammonia. Originally thought to be liver-specific, this protein has been found in other tissues as well. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Jul 2013]

GLS2 links:

SPRYD4 (HGNC:27468): (SPRY domain containing 4) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SPRYD4 links:

ENSG00000285528 (HGNC:):

ENSG00000285528 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3230464).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013267.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLS2	NM_013267.4	MANE Select	c.1057G>A	p.Val353Met	missense	Exon 12 of 18	NP_037399.2
SPRYD4	NM_207344.4	MANE Select	c.*5134C>T		3_prime_UTR	Exon 2 of 2	NP_997227.1	Q8WW59
GLS2	NM_001280797.2		c.262G>A	p.Val88Met	missense	Exon 11 of 17	NP_001267726.1	A0A087X004

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLS2	ENST00000311966.9	TSL:1 MANE Select	c.1057G>A	p.Val353Met	missense	Exon 12 of 18	ENSP00000310447.4	Q9UI32-1
SPRYD4	ENST00000338146.7	TSL:1 MANE Select	c.*5134C>T		3_prime_UTR	Exon 2 of 2	ENSP00000338034.5	Q8WW59
GLS2	ENST00000424141.6	TSL:1	n.*393G>A		non_coding_transcript_exon	Exon 11 of 17	ENSP00000416282.2	A8K0A6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456852

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25734

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108766

Other (OTH)

AF:

0.00

AC:

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0080

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

PhyloP100

5.0

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.52

REVEL

Benign

0.10

Sift

Benign

0.41

Sift4G

Benign

0.24

Polyphen

0.11

Vest4

0.59

MutPred

0.53

Gain of catalytic residue at E354 (P = 0.0028)

MVP

0.66

MPC

0.72

ClinPred

0.53

GERP RS

5.7

Varity_R

0.31

gMVP

0.56

Mutation Taster

=69/31

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over