Genetic Variant NM_013267.4:c.1742T>C (chr12-56471554-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B.

-12

BP4_StrongBA1

The NM_013267.4(GLS2):c.1742T>C(p.Leu581Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,613,616 control chromosomes in the GnomAD database, including 26,333 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L581F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 2024 hom., cov: 32)

Exomes 𝑓: 0.18 ( 24309 hom. )

Consequence

GLS2
NM_013267.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

107 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045092404).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLS2	NM_013267.4 link	c.1742T>C	p.Leu581Pro	missense_variant	Exon 18 of 18	ENST00000311966.9	NP_037399.2	Q9UI32-1
SPRYD4	NM_207344.4 link	c.*1977A>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000338146.7	NP_997227.1	Q8WW59

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLS2	ENST00000311966.9 link	c.1742T>C	p.Leu581Pro	missense_variant	Exon 18 of 18	1	NM_013267.4	ENSP00000310447.4	Q9UI32-1
SPRYD4	ENST00000338146.7 link	c.*1977A>G		3_prime_UTR_variant	Exon 2 of 2	1	NM_207344.4	ENSP00000338034.5	Q8WW59
ENSG00000285528	ENST00000648304.1 link	n.182+16383T>C		intron_variant	Intron 1 of 3			ENSP00000497190.1	A0A3B3IS89

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

22871

AN:

151890

Hom.:

2020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0634

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.205

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.0887

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.186

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.167

GnomAD2 exomes

AF:

0.172

AC:

43210

AN:

251184

AF XY:

0.171

show subpopulations

Gnomad AFR exome

AF:

0.0596

Gnomad AMR exome

AF:

0.235

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.0873

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.184

Gnomad OTH exome

AF:

0.192

GnomAD4 exome

AF:

0.178

AC:

260486

AN:

1461608

Hom.:

24309

Cov.:

AF XY:

0.179

AC XY:

129802

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0565

AC:

1892

AN:

33476

American (AMR)

AF:

0.232

AC:

10355

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

5138

AN:

26128

East Asian (EAS)

AF:

0.101

AC:

4011

AN:

39698

South Asian (SAS)

AF:

0.152

AC:

13139

AN:

86240

European-Finnish (FIN)

AF:

0.183

AC:

9763

AN:

53414

Middle Eastern (MID)

AF:

0.188

AC:

1083

AN:

5768

European-Non Finnish (NFE)

AF:

0.184

AC:

204764

AN:

1111814

Other (OTH)

AF:

0.171

AC:

10341

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

11367

22734

34101

45468

56835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7068

14136

21204

28272

35340

<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:

0.151

AC:

22879

AN:

152008

Hom.:

2024

Cov.:

AF XY:

0.152

AC XY:

11293

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.0633

AC:

2626

AN:

41458

American (AMR)

AF:

0.206

AC:

3135

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

644

AN:

3464

East Asian (EAS)

AF:

0.0882

AC:

456

AN:

5172

South Asian (SAS)

AF:

0.148

AC:

715

AN:

4816

European-Finnish (FIN)

AF:

0.186

AC:

1965

AN:

10546

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12638

AN:

67990

Other (OTH)

AF:

0.164

AC:

346

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

961

1922

2884

3845

4806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.173

Hom.:

10632

Bravo

AF:

0.148

TwinsUK

AF:

0.188

AC:

696

ALSPAC

AF:

0.177

AC:

684

ESP6500AA

AF:

0.0656

AC:

289

ESP6500EA

AF:

0.186

AC:

1601

ExAC

AF:

0.166

AC:

20157

Asia WGS

AF:

0.128

AC:

448

AN:

3478

EpiCase

AF:

0.204

EpiControl

AF:

0.201

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.7

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.095

.;.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.51

.;T;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;.;L

PhyloP100

1.1

PrimateAI

Benign

0.34

PROVEAN

Benign

0.98

.;.;N

REVEL

Benign

0.020

Sift

Benign

0.32

.;.;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.088

MPC

0.87

ClinPred

0.00035

GERP RS

3.1

Varity_R

0.064

gMVP

0.69

Mutation Taster

=93/7

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over