Genetic Variant TBX2:p.Gly56Asp (chr17-61400343-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005994.4(TBX2):c.167G>A(p.Gly56Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 856,908 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

TBX2
NM_005994.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.927

Publications

0 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: 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=0.2725863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX2	NM_005994.4 link	c.167G>A	p.Gly56Asp	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.167G>A	p.Gly56Asp	missense_variant	Exon 1 of 7	1	NM_005994.4	ENSP00000240328.3		Q13207

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000233

AC:

AN:

856908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

399210

show subpopulations

African (AFR)

AF:

0.0000619

AC:

AN:

16166

American (AMR)

AF:

0.00

AC:

AN:

1638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5590

East Asian (EAS)

AF:

0.00

AC:

AN:

4524

South Asian (SAS)

AF:

0.00

AC:

AN:

17570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1796

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

778970

Other (OTH)

AF:

0.0000351

AC:

AN:

28468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.167G>A (p.G56D) alteration is located in exon 1 (coding exon 1) of the TBX2 gene. This alteration results from a G to A substitution at nucleotide position 167, causing the glycine (G) at amino acid position 56 to be replaced by an aspartic acid (D). 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

Uncertain

0.44

BayesDel_addAF

Benign

0.0086

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.69

PhyloP100

0.93

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.38

REVEL

Benign

0.18

Sift

Benign

0.46

Sift4G

Benign

0.33

Polyphen

0.15

Vest4

0.30

MutPred

0.24

Loss of catalytic residue at G56 (P = 0.0352);

MVP

0.66

ClinPred

0.17

GERP RS

3.6

Varity_R

0.16

gMVP

0.52

Mutation Taster

=88/12

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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17-61400343-G-A

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