NM_013267.4:c.1742T>C

Variant summary

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

Score: -12 - Benign
-12
-12 -7 -6 -1 0 5 6 9 10 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

18

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

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
GLS2NM_013267.4 linkc.1742T>C p.Leu581Pro missense_variant Exon 18 of 18 ENST00000311966.9 NP_037399.2 Q9UI32-1
SPRYD4NM_207344.4 linkc.*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 Appris UniProt
GLS2ENST00000311966.9 linkc.1742T>C p.Leu581Pro missense_variant Exon 18 of 18 1 NM_013267.4 ENSP00000310447.4 Q9UI32-1
SPRYD4ENST00000338146.7 linkc.*1977A>G 3_prime_UTR_variant Exon 2 of 2 1 NM_207344.4 ENSP00000338034.5 Q8WW59
ENSG00000285528ENST00000648304.1 linkn.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.:
32
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.:
33
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
0
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
0
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.:
32
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:
66
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
0
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
0
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
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
7.7
DANN
Benign
0.87
DEOGEN2
Benign
0.095
.;.;T
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.023
N
LIST_S2
Benign
0.51
.;T;T
MetaRNN
Benign
0.0045
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
.;.;L
PhyloP100
1.1
PrimateAI
Benign
0.34
T
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
T
GERP RS
3.1
Varity_R
0.064
gMVP
0.69
Mutation Taster
=93/7
polymorphism (auto)

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

Other links and lift over

dbSNP: rs2657879; hg19: chr12-56865338; COSMIC: COSV57665756; COSMIC: COSV57665756; API