17-61400445-G-C

Variant names:

• chr17-61400445-G-C
• rs1379017045
• NM_005994.4:c.269G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_005994.4(TBX2):​c.269G>C​(p.Arg90Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,436,392 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TBX2 NM_005994.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.51
• 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX2	NM_005994.4	c.269G>C	p.Arg90Pro	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.269G>C	p.Arg90Pro	missense_variant	Exon 1 of 7	1	NM_005994.4	ENSP00000240328.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000482 AC: 1 AN: 207512 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000418 AC: 6 AN: 1436392 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712314

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

African (AFR) AF: 0.00 AC: 0 AN: 33126

American (AMR) AF: 0.00 AC: 0 AN: 41860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 38928

South Asian (SAS) AF: 0.00 AC: 0 AN: 82790

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.00000454 AC: 5 AN: 1101152

Other (OTH) AF: 0.00 AC: 0 AN: 59474

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000450), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.59
Sift	Benign	0.046	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.24		Loss of loop (P = 0.0112);
MVP		0.78
ClinPred		0.94	D
GERP RS		3.7
Varity_R		0.67
gMVP		0.84
Mutation Taster		=20/80	disease causing

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: rs1379017045; hg19: chr17-59477806;