NM_005994.4:c.346G>A

Variant names:

• chr17-61400522-G-A
• rs746678515
• NM_005994.4:c.346G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_005994.4(TBX2):​c.346G>A​(p.Asp116Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,593,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D116Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: TBX2 NM_005994.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• 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: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAd4 at 6 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 rank	MANE	Protein	UniProt
TBX2	NM_005994.4	c.346G>A	p.Asp116Asn	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.346G>A	p.Asp116Asn	missense_variant	Exon 1 of 7	1	NM_005994.4	ENSP00000240328.3

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152040 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: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000665 AC: 14 AN: 210650 AF XY: 0.0000876

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: 0.000152

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000333 AC: 48 AN: 1441544 Hom.: 0 Cov.: 32 AF XY: 0.0000350 AC XY: 25 AN XY: 714922

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 41812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25652

East Asian (EAS) AF: 0.00 AC: 0 AN: 39136

South Asian (SAS) AF: 0.00 AC: 0 AN: 82590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000435 AC: 48 AN: 1103040

Other (OTH) AF: 0.00 AC: 0 AN: 59704

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74240

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000753 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346G>A (p.D116N) 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 346, causing the aspartic acid (D) at amino acid position 116 to be replaced by an asparagine (N). 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	0.42
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.037	D
Polyphen		0.11	B
Vest4		0.44
MVP		0.65
ClinPred		0.34	T
GERP RS		2.9
Varity_R		0.51
gMVP		0.57
Mutation Taster		=35/65	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: rs746678515; hg19: chr17-59477883;