chr17-61400340-C-T

Position:

• chr17-61400340-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BS2_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. 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: 0.0000094 (0 hom.)
• Consequence: TBX2 NM_005994.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

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 Likely_benign. Variant got -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/exons	MANE	UniProt
TBX2	NM_005994.4	c.164C>T	p.Pro55Leu	missense_variant	1/7	ENST00000240328.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX2	ENST00000240328.4	c.164C>T	p.Pro55Leu	missense_variant	1/7	1	NM_005994.4	P1
TBX2	ENST00000419047.5	c.164C>T	p.Pro55Leu	missense_variant, NMD_transcript_variant	1/7	1
TBX2-AS1	ENST00000592009.1	n.41-6593G>A		intron_variant, non_coding_transcript_variant		3
TBX2	ENST00000477081.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000937 AC: 8 AN: 853636 Hom.: 0 Cov.: 30 AF XY: 0.00000755 AC XY: 3 AN XY: 397192

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: 0.00

Gnomad4 NFE exome AF: 0.00000901

Gnomad4 OTH exome AF: 0.0000354

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Jan 16, 2024

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	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.26
Sift	Benign	0.14	T
Sift4G	Benign	0.76	T
Polyphen		0.89	P
Vest4		0.18
MutPred		0.31		Loss of loop (P = 0.0203);
MVP		0.29
ClinPred		0.41	T
GERP RS		2.3
Varity_R		0.080
gMVP		0.39

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: rs1048308922; hg19: chr17-59477701;