12-56471626-A-C

Variant names:

• chr12-56471626-A-C
• NM_013267.4:c.1670T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_013267.4(GLS2):​c.1670T>G​(p.Leu557Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLS2 NM_013267.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.81

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLS2	NM_013267.4	c.1670T>G	p.Leu557Arg	missense_variant	Exon 18 of 18	ENST00000311966.9	NP_037399.2
SPRYD4	NM_207344.4	c.*2049A>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000338146.7	NP_997227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLS2	ENST00000311966.9	c.1670T>G	p.Leu557Arg	missense_variant	Exon 18 of 18	1	NM_013267.4	ENSP00000310447.4
SPRYD4	ENST00000338146.7	c.*2049A>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_207344.4	ENSP00000338034.5
ENSG00000285528	ENST00000648304.1	n.182+16311T>G		intron_variant	Intron 1 of 3			ENSP00000497190.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1670T>G (p.L557R) alteration is located in exon 18 (coding exon 18) of the GLS2 gene. This alteration results from a T to G substitution at nucleotide position 1670, causing the leucine (L) at amino acid position 557 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.4	.;.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.9	.;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.024	.;.;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.098	.;.;B
Vest4		0.83
MutPred		0.82		.;.;Gain of catalytic residue at I555 (P = 2e-04);
MVP		0.89
MPC		1.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56865410;