17-61400307-C-A

Variant names:

• chr17-61400307-C-A
• rs1390426411
• NM_005994.4:c.131C>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_005994.4(TBX2):​c.131C>A​(p.Pro44Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000349 in 1,087,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: TBX2 NM_005994.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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)

ENSG00000267131 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754
• BS2: High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX2	NM_005994.4	c.131C>A	p.Pro44Gln	missense_variant	Exon 1 of 7	ENST00000240328.4	NP_005985.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX2	ENST00000240328.4	c.131C>A	p.Pro44Gln	missense_variant	Exon 1 of 7	1	NM_005994.4	ENSP00000240328.3

Frequencies

GnomAD3 genomes AF: 0.0000273 AC: 4 AN: 146508 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000489

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: 0.0000304

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000361 AC: 34 AN: 941172 Hom.: 0 Cov.: 30 AF XY: 0.0000354 AC XY: 16 AN XY: 452486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000263

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000403

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000273 AC: 4 AN: 146508 Hom.: 0 Cov.: 32 AF XY: 0.0000281 AC XY: 2 AN XY: 71228

Gnomad4 AFR AF: 0.0000489

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000304

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TBX2 c.131C>A (p.Pro44Gln) results in a non-conservative amino acid change located in the DNA-binding domain (IPR046360) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 153504 control chromosomes (gnomAD, v3.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.131C>A in individuals affected with Vertebral Anomalies and Variable Endocrine and T-Cell Dysfunction and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.28		Loss of glycosylation at P44 (P = 0.0558);
MVP		0.85
ClinPred		0.75	D
GERP RS		3.3
Varity_R		0.43
gMVP		0.71

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: rs1390426411; hg19: chr17-59477668;