Genetic Variant GSTT2B:c.200+1G>A (chr22-23960293-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP5_ModerateBS2_Supporting

The NM_001080843.4(GSTT2B):c.200+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,611,566 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00030 ( 9 hom. )

Consequence

GSTT2B
NM_001080843.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.12

Publications

3 publications found

Variant links:

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]

GSTT2B links:

ENSG00000290199 (HGNC:):

ENSG00000290199 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 22-23960293-C-T is Pathogenic according to our data. Variant chr22-23960293-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3064991.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 9 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080843.4. 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
	GSTT2B	NM_001080843.4	MANE Select	c.200+1G>A		splice_donor intron	N/A	NP_001074312.1	P0CG30
	GSTT2B	NM_001363804.1		c.200+1G>A		splice_donor intron	N/A	NP_001350733.1	Q6ICJ4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSTT2B	ENST00000290765.9	TSL:1 MANE Select	c.200+1G>A	splice_donor intron	N/A	ENSP00000290765.4	P0CG30
GSTT2B	ENST00000404172.3	TSL:1	c.200+1G>A	splice_donor intron	N/A	ENSP00000385116.3	Q6ICJ4
GSTT2B	ENST00000895419.1		c.200+1G>A	splice_donor intron	N/A	ENSP00000565478.1

Frequencies

GnomAD3 genomes

AF:

0.000370

AC:

AN:

151320

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000727

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00609

Gnomad EAS

AF:

0.000392

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000281

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.0247

AC:

782

AN:

31660

AF XY:

0.0233

show subpopulations

Gnomad AFR exome

AF:

0.0451

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.0263

Gnomad EAS exome

AF:

0.0427

Gnomad FIN exome

AF:

0.0125

Gnomad NFE exome

AF:

0.0227

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.000295

AC:

431

AN:

1460138

Hom.:

Cov.:

AF XY:

0.000332

AC XY:

241

AN XY:

726408

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33464

American (AMR)

AF:

0.000157

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00649

AC:

169

AN:

26026

East Asian (EAS)

AF:

0.000202

AC:

AN:

39526

South Asian (SAS)

AF:

0.000534

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.000131

AC:

145

AN:

1110798

Other (OTH)

AF:

0.000680

AC:

AN:

60310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000376

AC:

AN:

151428

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

AN XY:

74032

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000966

AC:

AN:

41390

American (AMR)

AF:

0.000131

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00609

AC:

AN:

3446

East Asian (EAS)

AF:

0.000393

AC:

AN:

5090

South Asian (SAS)

AF:

0.00104

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000281

AC:

AN:

67596

Other (OTH)

AF:

0.000477

AC:

AN:

2096

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000401901), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.383

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00358

Hom.:

ExAC

AF:

0.00641

AC:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Megalencephalic leukoencephalopathy with subcortical cysts 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Benign

0.96

Eigen

Uncertain

0.50

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.71

PhyloP100

3.1

GERP RS

1.8

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: 23

DS_DL_spliceai

0.99

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over