NM_013267.4:c.1742T>C

Variant names:

• chr12-56471554-A-G
• rs2657879
• NM_013267.4:c.1742T>C

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 107 publications found

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]

ENSG00000285528 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013267.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS2	NM_013267.4	MANE Select	c.1742T>C	p.Leu581Pro	missense	Exon 18 of 18	NP_037399.2
	SPRYD4	NM_207344.4	MANE Select	c.*1977A>G		3_prime_UTR	Exon 2 of 2	NP_997227.1	Q8WW59
	GLS2	NM_001280797.2		c.947T>C	p.Leu316Pro	missense	Exon 17 of 17	NP_001267726.1	A0A087X004

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS2	ENST00000311966.9	TSL:1 MANE Select	c.1742T>C	p.Leu581Pro	missense	Exon 18 of 18	ENSP00000310447.4	Q9UI32-1
	SPRYD4	ENST00000338146.7	TSL:1 MANE Select	c.*1977A>G		3_prime_UTR	Exon 2 of 2	ENSP00000338034.5	Q8WW59
	GLS2	ENST00000390288.6	TSL:1	n.790T>C		non_coding_transcript_exon	Exon 2 of 2

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

GnomAD2 exomes AF: 0.172 AC: 43210 AN: 251184 AF XY: 0.171

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

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

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

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

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 v4.9

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
MetaRNN	Benign	0.0045	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
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

Other links and lift over

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