Genetic Variant TOX2:p.Gly155Arg (chr20-44051357-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001098797.2(TOX2):c.463G>C(p.Gly155Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TOX2
NM_001098797.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.12

Publications

0 publications found

Variant links:

Genes affected

TOX2 (HGNC:16095): (TOX high mobility group box family member 2) Enables transcription coactivator activity. Involved in positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TOX2 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26409674).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098797.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOX2	NM_001098797.2	MANE Select	c.463G>C	p.Gly155Arg	missense	Exon 4 of 9	NP_001092267.1	Q96NM4-4
TOX2	NM_001098798.2		c.490G>C	p.Gly164Arg	missense	Exon 4 of 8	NP_001092268.1	Q96NM4-1
TOX2	NM_001098796.2		c.337G>C	p.Gly113Arg	missense	Exon 4 of 9	NP_001092266.1	Q96NM4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOX2	ENST00000341197.9	TSL:2 MANE Select	c.463G>C	p.Gly155Arg	missense	Exon 4 of 9	ENSP00000344724.3	Q96NM4-4
TOX2	ENST00000372999.5	TSL:1	c.337G>C	p.Gly113Arg	missense	Exon 5 of 10	ENSP00000362090.1	Q96NM4-3
TOX2	ENST00000864666.1		c.463G>C	p.Gly155Arg	missense	Exon 4 of 10	ENSP00000534725.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247508

AF XY:

0.00000745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000903

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461328

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726920

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111688

Other (OTH)

AF:

0.00

AC:

AN:

60378

⚠️ 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0069

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.025

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

PhyloP100

5.1

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.38

REVEL

Benign

0.17

Sift

Benign

0.57

Sift4G

Benign

0.53

Polyphen

0.99

Vest4

0.48

MutPred

0.25

Gain of solvent accessibility (P = 0.0789)

MVP

0.19

MPC

1.1

ClinPred

0.59

GERP RS

5.6

Varity_R

0.14

gMVP

0.55

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over