22-23960298-C-T

Variant names:

• chr22-23960298-C-T
• rs781652428
• NM_001080843.4:c.196G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_001080843.4(GSTT2B):​c.196G>A​(p.Glu66Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0019 in 1,612,624 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: GSTT2B NM_001080843.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04

Genes affected

GSTT2B (HGNC:33437): (glutathione S-transferase theta 2B) The protein encoded by this gene, glutathione S-transferase (GST) theta 2B (GSTT2B), is a member of a superfamily of proteins that catalyze the conjugation of reduced glutathione to a variety of electrophilic and hydrophobic compounds. Human GSTs can be divided into five main classes: alpha, mu, pi, theta, and zeta. The theta class includes GSTT1, GSTT2, and GSTT2B. GSTT2 and GSTT2B are nearly identical to each other, and share 55% amino acid identity with GSTT1. All three genes may play a role in human carcinogenesis. The GSTT2B gene is a pseudogene in some populations. [provided by RefSeq, Sep 2015]

ENSG00000290199 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3751099).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSTT2B	NM_001080843.4	c.196G>A	p.Glu66Lys	missense_variant	Exon 2 of 5	ENST00000290765.9	NP_001074312.1
GSTT2B	NM_001363804.1	c.196G>A	p.Glu66Lys	missense_variant	Exon 2 of 5		NP_001350733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSTT2B	ENST00000290765.9	c.196G>A	p.Glu66Lys	missense_variant	Exon 2 of 5	1	NM_001080843.4	ENSP00000290765.4
GSTT2B	ENST00000404172.3	c.196G>A	p.Glu66Lys	missense_variant	Exon 2 of 5	1		ENSP00000385116.3
ENSG00000290199	ENST00000703580.1	n.309+13470G>A		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 235 AN: 151756 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00264

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00196 AC: 78 AN: 39848 Hom.: 0 AF XY: 0.00204 AC XY: 41 AN XY: 20128

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00208

Gnomad FIN exome AF: 0.000427

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00193 AC: 2824 AN: 1460750 Hom.: 2 Cov.: 32 AF XY: 0.00196 AC XY: 1427 AN XY: 726706

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00463

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00154 AC: 234 AN: 151874 Hom.: 0 Cov.: 30 AF XY: 0.00132 AC XY: 98 AN XY: 74222

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00664

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00264

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.000598 Hom.: 0

ExAC AF: 0.000212 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196G>A (p.E66K) alteration is located in exon 2 (coding exon 2) of the GSTT2B gene. This alteration results from a G to A substitution at nucleotide position 196, causing the glutamic acid (E) at amino acid position 66 to be replaced by a lysine (K). 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	0.67
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.1	H;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.044	D;D
Polyphen		0.96	D;D
Vest4		0.77
MutPred		0.92		Gain of methylation at E66 (P = 0.01);Gain of methylation at E66 (P = 0.01);
MVP		0.84
MPC		2.1
ClinPred		0.16	T
GERP RS		2.4
Varity_R		0.86
gMVP		0.86

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: rs781652428; hg19: chr22-24302485;