1-109669533-C-G

Variant names:

• chr1-109669533-C-G
• NM_000848.4:c.322C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000848.4(GSTM2):​c.322C>G​(p.Arg108Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GSTM2 NM_000848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.970

Genes affected

GSTM2 (HGNC:4634): (glutathione S-transferase mu 2) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSTM2	NM_000848.4	c.322C>G	p.Arg108Gly	missense_variant	Exon 5 of 8	ENST00000241337.9	NP_000839.1
GSTM2	NM_001142368.2	c.322C>G	p.Arg108Gly	missense_variant	Exon 5 of 9		NP_001135840.1
GSTM2	XR_007059236.1	n.381C>G		non_coding_transcript_exon_variant	Exon 5 of 7
GSTM2	XR_007059237.1	n.381C>G		non_coding_transcript_exon_variant	Exon 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSTM2	ENST00000241337.9	c.322C>G	p.Arg108Gly	missense_variant	Exon 5 of 8	1	NM_000848.4	ENSP00000241337.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726130

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322C>G (p.R108G) alteration is located in exon 5 (coding exon 5) of the GSTM2 gene. This alteration results from a C to G substitution at nucleotide position 322, causing the arginine (R) at amino acid position 108 to be replaced by a glycine (G). 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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.018	.;T;T;.;T;T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.61	T;T;T;.;T;T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.4	M;.;.;M;M;.;.;.
PROVEAN	Pathogenic	-4.8	D;D;.;D;D;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0080	D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.052	T;D;T;T;T;D;D;T
Polyphen		0.91	.;.;.;.;P;.;.;.
Vest4		0.70
MutPred		0.69		Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);.;Gain of loop (P = 0.0502);
MVP		0.18
MPC		1.5
ClinPred		0.93	D
GERP RS		-1.4
Varity_R		0.77
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr1-110212155;