rs1364709483

chr17-61400235-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PP5_Very_Strong BS2

The NM_005994.4(TBX2):c.59G>A(p.Arg20Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000051 in 1,215,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: TBX2 NM_005994.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.03

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]

(HGNC:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP5: Variant 17-61400235-G-A is Pathogenic according to our data. Variant chr17-61400235-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX2	NM_005994.4	c.59G>A	p.Arg20Gln	missense_variant	1/7	ENST00000240328.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX2	ENST00000240328.4	c.59G>A	p.Arg20Gln	missense_variant	1/7	1	NM_005994.4	P1
	ENST00000585765.1	n.9C>T		non_coding_transcript_exon_variant	1/4	5
TBX2	ENST00000419047.5	c.59G>A	p.Arg20Gln	missense_variant, NMD_transcript_variant	1/7	1
TBX2-AS1	ENST00000592009.1	n.41-6488C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000614 AC: 9 AN: 146628 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

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: 0.000121

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000496 AC: 53 AN: 1069092 Hom.: 0 Cov.: 30 AF XY: 0.0000493 AC XY: 26 AN XY: 527916

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: 0.00

Gnomad4 FIN exome AF: 0.0000809

Gnomad4 NFE exome AF: 0.0000575

Gnomad4 OTH exome AF: 0.0000272

GnomAD4 genome AF: 0.0000614 AC: 9 AN: 146628 Hom.: 0 Cov.: 32 AF XY: 0.0000421 AC XY: 3 AN XY: 71312

Gnomad4 AFR AF: 0.0000244

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: 0.000121

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vertebral anomalies and variable endocrine and T-cell dysfunction Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2022	- -

TBX2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Feb 24, 2016

This family has been reported in PMID: 29726930 (family 1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.33
MutPred		0.28		Loss of methylation at R20 (P = 0.0306);
MVP		0.49
ClinPred		0.95	D
GERP RS		2.5
Varity_R		0.68
gMVP		0.76

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: rs1364709483; hg19: chr17-59477596;