chr20-44054303-C-T

Variant names:

• chr20-44054303-C-T
• rs561015693
• NM_001098797.2:c.656C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001098797.2(TOX2):​c.656C>T​(p.Ser219Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,607,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TOX2 NM_001098797.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.065125495).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOX2	NM_001098797.2	MANE Select	c.656C>T	p.Ser219Leu	missense	Exon 5 of 9	NP_001092267.1	Q96NM4-4
	TOX2	NM_001098798.2		c.683C>T	p.Ser228Leu	missense	Exon 5 of 8	NP_001092268.1	Q96NM4-1
	TOX2	NM_001098796.2		c.530C>T	p.Ser177Leu	missense	Exon 5 of 9	NP_001092266.1	Q96NM4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOX2	ENST00000341197.9	TSL:2 MANE Select	c.656C>T	p.Ser219Leu	missense	Exon 5 of 9	ENSP00000344724.3	Q96NM4-4
	TOX2	ENST00000372999.5	TSL:1	c.530C>T	p.Ser177Leu	missense	Exon 6 of 10	ENSP00000362090.1	Q96NM4-3
	TOX2	ENST00000864666.1		c.656C>T	p.Ser219Leu	missense	Exon 5 of 10	ENSP00000534725.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000335 AC: 8 AN: 239070 AF XY: 0.0000309

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1455734 Hom.: 0 Cov.: 31 AF XY: 0.0000263 AC XY: 19 AN XY: 723738

African (AFR) AF: 0.000301 AC: 10 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 43770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39348

South Asian (SAS) AF: 0.0000701 AC: 6 AN: 85562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1108786

Other (OTH) AF: 0.0000166 AC: 1 AN: 60162

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41480

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000495 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.048
Sift	Benign	0.074	T
Sift4G	Benign	0.36	T
Polyphen		0.81	P
Vest4		0.25
MutPred		0.29		Loss of glycosylation at S228 (P = 0.0189)
MVP		0.043
MPC		0.26
ClinPred		0.13	T
GERP RS		5.3
PromoterAI		-0.030	Neutral
Varity_R		0.16
gMVP		0.21
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs561015693; hg19: chr20-42682943; COSMIC: COSV57888433; COSMIC: COSV57888433;