chr17-61400343-G-A

Position:

• chr17-61400343-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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. 12/20 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.927

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

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
TBX2	NM_005994.4	c.167G>A	p.Gly56Asp	missense_variant	1/7	ENST00000240328.4	NP_005985.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX2	ENST00000240328.4	c.167G>A	p.Gly56Asp	missense_variant	1/7	1	NM_005994.4	ENSP00000240328	P1
TBX2	ENST00000419047.5	c.167G>A	p.Gly56Asp	missense_variant, NMD_transcript_variant	1/7	1		ENSP00000404781
TBX2-AS1	ENST00000592009.1	n.41-6596C>T		intron_variant, non_coding_transcript_variant		3
TBX2	ENST00000477081.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000233 AC: 2 AN: 856908 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 399210

Gnomad4 AFR exome AF: 0.0000619

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000351

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.18
Sift	Benign	0.46	T
Sift4G	Benign	0.33	T
Polyphen		0.15	B
Vest4		0.30
MutPred		0.24		Loss of catalytic residue at G56 (P = 0.0352);
MVP		0.66
ClinPred		0.17	T
GERP RS		3.6
Varity_R		0.16
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-59477704;