rs6577

Positions:

• chr6-52750617-T-G

Variant summary

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

The NM_000846.5(GSTA2):​c.629A>C​(p.Glu210Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0858 in 1,613,556 control chromosomes in the GnomAD database, including 18,704 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.

• Frequency:
  • Genomes: 𝑓 0.22 (8405 hom., cov: 33)
  • Exomes 𝑓: 0.072 (10299 hom.)
• Consequence: GSTA2 NM_000846.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26

Genes affected

GSTA2 (HGNC:4627): (glutathione S-transferase alpha 2) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. These enzymes function in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding these enzymes 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 some drugs. 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-tranferase belonging to the alpha class. The alpha class genes, located in a cluster mapped to chromosome 6, are the most abundantly expressed glutathione S-transferases in liver. In addition to metabolizing bilirubin and certain anti-cancer drugs in the liver, the alpha class of these enzymes exhibit glutathione peroxidase activity thereby protecting the cells from reactive oxygen species and the products of peroxidation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.5818906E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSTA2	NM_000846.5	c.629A>C	p.Glu210Ala	missense_variant	7/7	ENST00000493422.3	NP_000837.3
GSTA2	XM_047418684.1	c.629A>C	p.Glu210Ala	missense_variant	8/8		XP_047274640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSTA2	ENST00000493422.3	c.629A>C	p.Glu210Ala	missense_variant	7/7	1	NM_000846.5	ENSP00000420168	P1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33578 AN: 152068 Hom.: 8363 Cov.: 33

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0994

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0859

Gnomad FIN AF: 0.0569

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.183

GnomAD3 exomes AF: 0.106 AC: 26574 AN: 251346 Hom.: 3980 AF XY: 0.0943 AC XY: 12808 AN XY: 135844

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.0647

Gnomad ASJ exome AF: 0.0958

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.0724

Gnomad FIN exome AF: 0.0564

Gnomad NFE exome AF: 0.0546

Gnomad OTH exome AF: 0.0847

GnomAD4 exome AF: 0.0717 AC: 104802 AN: 1461370 Hom.: 10299 Cov.: 31 AF XY: 0.0703 AC XY: 51093 AN XY: 726982

Gnomad4 AFR exome AF: 0.649

Gnomad4 AMR exome AF: 0.0694

Gnomad4 ASJ exome AF: 0.0927

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.0731

Gnomad4 FIN exome AF: 0.0513

Gnomad4 NFE exome AF: 0.0490

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.221 AC: 33671 AN: 152186 Hom.: 8405 Cov.: 33 AF XY: 0.217 AC XY: 16132 AN XY: 74404

Gnomad4 AFR AF: 0.617

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.0994

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.0855

Gnomad4 FIN AF: 0.0569

Gnomad4 NFE AF: 0.0538

Gnomad4 OTH AF: 0.182

Alfa AF: 0.127 Hom.: 1713

Bravo AF: 0.243

TwinsUK AF: 0.0485 AC: 180

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.601 AC: 2648

ESP6500EA AF: 0.0571 AC: 491

ExAC AF: 0.115 AC: 13966

Asia WGS AF: 0.136 AC: 472 AN: 3474

EpiCase AF: 0.0622

EpiControl AF: 0.0577

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.052
DANN	Benign	0.63
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.0083	T
MetaRNN	Benign	0.0000046	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.84	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.015
Sift	Benign	0.36	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.019
ClinPred		0.0050	T
GERP RS		-0.13
Varity_R		0.087
gMVP		0.26

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: rs6577; hg19: chr6-52615415; COSMIC: COSV72414734;