chr20-44051529-C-A

Variant names:

• chr20-44051529-C-A
• rs375617057
• NM_001098797.2:c.635C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001098797.2(TOX2):​c.635C>A​(p.Ser212*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000138 in 1,445,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TOX2 NM_001098797.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.01
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.635C>A	p.Ser212*	stop_gained	Exon 4 of 9	NP_001092267.1	Q96NM4-4
	TOX2	NM_001098798.2		c.662C>A	p.Ser221*	stop_gained	Exon 4 of 8	NP_001092268.1	Q96NM4-1
	TOX2	NM_001098796.2		c.509C>A	p.Ser170*	stop_gained	Exon 4 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.635C>A	p.Ser212*	stop_gained	Exon 4 of 9	ENSP00000344724.3	Q96NM4-4
	TOX2	ENST00000372999.5	TSL:1	c.509C>A	p.Ser170*	stop_gained	Exon 5 of 10	ENSP00000362090.1	Q96NM4-3
	TOX2	ENST00000864666.1		c.635C>A	p.Ser212*	stop_gained	Exon 4 of 10	ENSP00000534725.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445882 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 716578

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

African (AFR) AF: 0.00 AC: 0 AN: 33194

American (AMR) AF: 0.00 AC: 0 AN: 43930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25406

East Asian (EAS) AF: 0.00 AC: 0 AN: 39336

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5072

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101692

Other (OTH) AF: 0.00 AC: 0 AN: 59538

⚠️ 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.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		4.0
Vest4		0.25
GERP RS		5.7
Mutation Taster		=13/187	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs375617057; hg19: chr20-42680169;