20-44051462-T-C

Variant names:

• chr20-44051462-T-C
• rs1333219336
• NM_001098797.2:c.568T>C

Variant summary

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

The NM_001098797.2(TOX2):​c.568T>C​(p.Ser190Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOX2 NM_001098797.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

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]

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
TOX2	NM_001098797.2	c.568T>C	p.Ser190Pro	missense_variant	Exon 4 of 9	ENST00000341197.9	NP_001092267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOX2	ENST00000341197.9	c.568T>C	p.Ser190Pro	missense_variant	Exon 4 of 9	2	NM_001098797.2	ENSP00000344724.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568T>C (p.S190P) alteration is located in exon 4 (coding exon 4) of the TOX2 gene. This alteration results from a T to C substitution at nucleotide position 568, causing the serine (S) at amino acid position 190 to be replaced by a proline (P). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.2	.;.;.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Benign	0.26
Sift	Benign	0.043	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.70
MutPred		0.32		.;.;.;Loss of phosphorylation at S199 (P = 0.0032);
MVP		0.13
MPC		1.1
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.65
gMVP		0.56

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: rs1333219336; hg19: chr20-42680102;