12-56471554-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013267.4(GLS2):​c.1742T>A​(p.Leu581His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GLS2
NM_013267.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14
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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15121159).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GLS2NM_013267.4 linkuse as main transcriptc.1742T>A p.Leu581His missense_variant 18/18 ENST00000311966.9
SPRYD4NM_207344.4 linkuse as main transcriptc.*1977A>T 3_prime_UTR_variant 2/2 ENST00000338146.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GLS2ENST00000311966.9 linkuse as main transcriptc.1742T>A p.Leu581His missense_variant 18/181 NM_013267.4 P1Q9UI32-1
SPRYD4ENST00000338146.7 linkuse as main transcriptc.*1977A>T 3_prime_UTR_variant 2/21 NM_207344.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461800
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727198
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
14
DANN
Benign
0.75
DEOGEN2
Benign
0.14
.;.;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.34
N
LIST_S2
Benign
0.72
.;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
.;.;L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
0.22
.;.;N
REVEL
Benign
0.047
Sift
Benign
0.13
.;.;T
Sift4G
Benign
0.13
T;T;T
Polyphen
0.0
.;.;B
Vest4
0.22
MutPred
0.41
.;.;Loss of stability (P = 0.0206);
MVP
0.34
MPC
0.71
ClinPred
0.082
T
GERP RS
3.1
Varity_R
0.052
gMVP
0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2657879; hg19: chr12-56865338; API