12-56471554-A-G

Position:

• chr12-56471554-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
GLS2	NM_013267.4	c.1742T>C	p.Leu581Pro	missense_variant	18/18	ENST00000311966.9
SPRYD4	NM_207344.4	c.*1977A>G		3_prime_UTR_variant	2/2	ENST00000338146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLS2	ENST00000311966.9	c.1742T>C	p.Leu581Pro	missense_variant	18/18	1	NM_013267.4	P1
SPRYD4	ENST00000338146.7	c.*1977A>G		3_prime_UTR_variant	2/2	1	NM_207344.4	P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22871 AN: 151890 Hom.: 2020 Cov.: 32

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

GnomAD3 exomes AF: 0.172 AC: 43210 AN: 251184 Hom.: 4066 AF XY: 0.171 AC XY: 23260 AN XY: 135748

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 SAS exome AF: 0.149

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

Gnomad4 AFR exome AF: 0.0565

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.184

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.151 AC: 22879 AN: 152008 Hom.: 2024 Cov.: 32 AF XY: 0.152 AC XY: 11293 AN XY: 74288

Gnomad4 AFR AF: 0.0633

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.186

Gnomad4 EAS AF: 0.0882

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.164

Alfa AF: 0.178 Hom.: 5667

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
MutationTaster	Benign	1.0	P
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

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

Other links and lift over

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