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. 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

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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