NM_005994.4:c.22G>A

Variant names:

• chr17-61400198-G-A
• rs1246452882
• NM_005994.4:c.22G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005994.4(TBX2):​c.22G>A​(p.Ala8Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,161,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: TBX2 NM_005994.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14
• Publications: 2 publications found

Genes affected

TBX2 (HGNC:11597): (T-box transcription factor 2) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product is the human homolog of mouse Tbx2, and shares strong sequence similarity with Drosophila omb protein. Expression studies indicate that this gene may have a potential role in tumorigenesis as an immortalizing agent. Transcript heterogeneity due to alternative polyadenylation has been noted for this gene. [provided by RefSeq, Jul 2008]

TBX2-AS1 (HGNC:50355): (TBX2 antisense RNA 1)

ACMG classification

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=0.28608775).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005994.4. 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
	TBX2	NM_005994.4	MANE Select	c.22G>A	p.Ala8Thr	missense	Exon 1 of 7	NP_005985.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX2	ENST00000240328.4	TSL:1 MANE Select	c.22G>A	p.Ala8Thr	missense	Exon 1 of 7	ENSP00000240328.3	Q13207
	TBX2	ENST00000419047.5	TSL:1	n.22G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000404781.1	F8WCM9
	TBX2	ENST00000964762.1		c.22G>A	p.Ala8Thr	missense	Exon 1 of 8	ENSP00000634821.1

Frequencies

GnomAD3 genomes AF: 0.00000683 AC: 1 AN: 146500 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000296 AC: 3 AN: 1014628 Hom.: 0 Cov.: 30 AF XY: 0.00000402 AC XY: 2 AN XY: 496954

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

African (AFR) AF: 0.0000510 AC: 1 AN: 19620

American (AMR) AF: 0.00 AC: 0 AN: 17918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11666

East Asian (EAS) AF: 0.00 AC: 0 AN: 9228

South Asian (SAS) AF: 0.0000200 AC: 1 AN: 50030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2966

European-Non Finnish (NFE) AF: 0.00000116 AC: 1 AN: 859418

Other (OTH) AF: 0.00 AC: 0 AN: 34294

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00846340), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000683 AC: 1 AN: 146500 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71210

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

African (AFR) AF: 0.0000245 AC: 1 AN: 40892

American (AMR) AF: 0.00 AC: 0 AN: 14770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65892

Other (OTH) AF: 0.00 AC: 0 AN: 2022

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.041	D
Polyphen		0.15	B
Vest4		0.18
MutPred		0.21		Gain of glycosylation at A8 (P = 0.0067)
MVP		0.32
ClinPred		0.94	D
GERP RS		3.2
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.33
gMVP		0.45
Mutation Taster		=84/16	polymorphism

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: rs1246452882; hg19: chr17-59477559;