17-61400362-C-CGCG

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_005994.4(TBX2):c.201_203dup(p.Ala70dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,033,824 control chromosomes in the GnomAD database, including 10 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: TBX2 NM_005994.4 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.53

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 Benign. Variant got -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005994.4
• BP6: Variant 17-61400362-C-CGCG is Benign according to our data. Variant chr17-61400362-C-CGCG is described in ClinVar as [Likely_benign]. Clinvar id is 3055119.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00537 (790/147004) while in subpopulation AFR AF= 0.0178 (730/41008). AF 95% confidence interval is 0.0167. There are 7 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 790 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX2	NM_005994.4	c.201_203dup	p.Ala70dup	inframe_insertion	1/7	ENST00000240328.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX2	ENST00000240328.4	c.201_203dup	p.Ala70dup	inframe_insertion	1/7	1	NM_005994.4	P1
TBX2	ENST00000419047.5	c.201_203dup	p.Ala70dup	inframe_insertion, NMD_transcript_variant	1/7	1
TBX2-AS1	ENST00000592009.1	n.41-6616_41-6615insCGC		intron_variant, non_coding_transcript_variant		3
TBX2	ENST00000477081.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 790 AN: 146900 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00271

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000116

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000136

Gnomad OTH AF: 0.00346

GnomAD3 exomes AF: 0.000539 AC: 1 AN: 1854 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1036

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000628

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000536 AC: 475 AN: 886820 Hom.: 3 Cov.: 30 AF XY: 0.000511 AC XY: 212 AN XY: 415132

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000561

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000659

GnomAD4 genome AF: 0.00537 AC: 790 AN: 147004 Hom.: 7 Cov.: 32 AF XY: 0.00534 AC XY: 382 AN XY: 71556

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.00270

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000116

Gnomad4 NFE AF: 0.000136

Gnomad4 OTH AF: 0.00342

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TBX2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs539663160; hg19: chr17-59477723;