20-44054313-G-T

Position:

• chr20-44054313-G-T

Variant summary

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

The NM_001098797.2(TOX2):​c.666G>T​(p.Lys222Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOX2 NM_001098797.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55

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/exons	MANE	Protein	UniProt
TOX2	NM_001098797.2	c.666G>T	p.Lys222Asn	missense_variant	5/9	ENST00000341197.9	NP_001092267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOX2	ENST00000341197.9	c.666G>T	p.Lys222Asn	missense_variant	5/9	2	NM_001098797.2	ENSP00000344724	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

May 04, 2017

This 6 year old male with macrocephaly and autism was found to carry a de novo variant in the TOX2 gene. At the time of report, this gene is not clearly associated with any known disease. The variant is absent from population databases. Computational models predict the variant to be damaging. Additionally, a variant in the PTEN gene was identified in this family which is the likely explanation for his clinical and family history. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;.;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.68
MutPred		0.36		.;.;.;Loss of ubiquitination at K231 (P = 0.0037);
MVP		0.47
MPC		1.1
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.47
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1569140429; hg19: chr20-42682953;