17-61400339-C-T

Variant names:

• chr17-61400339-C-T
• rs1433871216
• NM_005994.4:c.163C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005994.4(TBX2):​c.163C>T​(p.Pro55Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000299 in 1,002,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P55L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: TBX2 NM_005994.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57
• Publications: 0 publications found

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

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=0.28502142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX2	NM_005994.4	c.163C>T	p.Pro55Ser	missense_variant	Exon 1 of 7	ENST00000240328.4	NP_005985.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX2	ENST00000240328.4	c.163C>T	p.Pro55Ser	missense_variant	Exon 1 of 7	1	NM_005994.4	ENSP00000240328.3

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 146702 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000303

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000117 AC: 1 AN: 855942 Hom.: 0 Cov.: 29 AF XY: 0.00000251 AC XY: 1 AN XY: 398984

African (AFR) AF: 0.00 AC: 0 AN: 16128

American (AMR) AF: 0.00 AC: 0 AN: 1646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5582

East Asian (EAS) AF: 0.00 AC: 0 AN: 4444

South Asian (SAS) AF: 0.0000561 AC: 1 AN: 17820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1830

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 778154

Other (OTH) AF: 0.00 AC: 0 AN: 28366

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 146702 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71338

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40910

American (AMR) AF: 0.00 AC: 0 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000303 AC: 2 AN: 65956

Other (OTH) AF: 0.00 AC: 0 AN: 2018

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.163C>T (p.P55S) 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 163, causing the proline (P) at amino acid position 55 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.14	N
REVEL	Benign	0.20
Sift	Benign	0.076	T
Sift4G	Benign	0.44	T
Polyphen		0.42	B
Vest4		0.22
MutPred		0.26		Gain of glycosylation at P55 (P = 0.0185);
MVP		0.39
ClinPred		0.49	T
GERP RS		3.3
PromoterAI		0.025	Neutral
Varity_R		0.075
gMVP		0.36
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1433871216; hg19: chr17-59477700;