Genetic Variant TBX2:p.Pro55Leu (chr17-61400340-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS2_Supporting

The NM_005994.4(TBX2):c.164C>T(p.Pro55Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000937 in 853,636 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P55S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

TBX2
NM_005994.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.38

Publications

2 publications found

Variant links:

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 links:

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

TBX2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29539523).

BS2

High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX2	NM_005994.4 link	c.164C>T	p.Pro55Leu	missense_variant	Exon 1 of 7	ENST00000240328.4	NP_005985.3	Q13207A0A024QZ86

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX2	ENST00000240328.4 link	c.164C>T	p.Pro55Leu	missense_variant	Exon 1 of 7	1	NM_005994.4	ENSP00000240328.3		Q13207

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000937

AC:

AN:

853636

Hom.:

Cov.:

AF XY:

0.00000755

AC XY:

AN XY:

397192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16110

American (AMR)

AF:

0.00

AC:

AN:

1562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5530

East Asian (EAS)

AF:

0.00

AC:

AN:

4380

South Asian (SAS)

AF:

0.00

AC:

AN:

17522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1794

European-Non Finnish (NFE)

AF:

0.00000901

AC:

AN:

776540

Other (OTH)

AF:

0.0000354

AC:

AN:

28272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.164C>T (p.P55L) alteration is located in exon 1 (coding exon 1) of the TBX2 gene. This alteration results from a C to T substitution at nucleotide position 164, causing the proline (P) at amino acid position 55 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.39

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.90

PhyloP100

4.4

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.49

REVEL

Benign

0.26

Sift

Benign

0.14

Sift4G

Benign

0.76

Polyphen

0.89

Vest4

0.18

MutPred

0.31

Loss of loop (P = 0.0203);

MVP

0.29

ClinPred

0.41

GERP RS

2.3

PromoterAI

0.0058

Neutral

(source)

Varity_R

0.080

gMVP

0.39

Mutation Taster

=96/4

polymorphism

(source)

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

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17-61400340-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over