6-149380399-A-T

Variant names:

• chr6-149380399-A-T
• rs12204461
• NM_001292034.3:c.1603+881A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001292034.3(TAB2):​c.1603+881A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,114 control chromosomes in the GnomAD database, including 4,403 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4403 hom., cov: 32)
• Consequence: TAB2 NM_001292034.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• Publications: 6 publications found

Genes affected

TAB2 (HGNC:17075): (TGF-beta activated kinase 1 (MAP3K7) binding protein 2) The protein encoded by this gene is an activator of MAP3K7/TAK1, which is required for for the IL-1 induced activation of nuclear factor kappaB and MAPK8/JNK. This protein forms a kinase complex with TRAF6, MAP3K7 and TAB1, and it thus serves as an adaptor that links MAP3K7 and TRAF6. This protein, along with TAB1 and MAP3K7, also participates in the signal transduction induced by TNFSF11/RANKl through the activation of the receptor activator of NF-kappaB (TNFRSF11A/RANK), which may regulate the development and function of osteoclasts. Studies of the related mouse protein indicate that it functions to protect against liver damage caused by chemical stressors. Mutations in this gene cause congenital heart defects, multiple types, 2 (CHTD2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

TAB2 Gene-Disease associations (from GenCC):

• chromosome 6q24-q25 deletion syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• congenital heart defects, multiple types, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• polyvalvular heart disease syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292034.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAB2	NM_001292034.3	MANE Select	c.1603+881A>T		intron	N/A	NP_001278963.1	Q9NYJ8-1
	TAB2	NM_001369506.1		c.1603+881A>T		intron	N/A	NP_001356435.1	Q9NYJ8-1
	TAB2	NM_015093.6		c.1603+881A>T		intron	N/A	NP_055908.1	Q9NYJ8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAB2	ENST00000637181.2	TSL:1 MANE Select	c.1603+881A>T		intron	N/A	ENSP00000490618.1	Q9NYJ8-1
	TAB2	ENST00000470466.5	TSL:1	n.*202+256A>T		intron	N/A	ENSP00000432709.1	Q9NYJ8-2
	TAB2	ENST00000367456.5	TSL:5	c.1603+881A>T		intron	N/A	ENSP00000356426.1	Q9NYJ8-1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35695 AN: 151998 Hom.: 4394 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0877

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.255

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.235 AC: 35731 AN: 152114 Hom.: 4403 Cov.: 32 AF XY: 0.232 AC XY: 17278 AN XY: 74356

African (AFR) AF: 0.220 AC: 9145 AN: 41492

American (AMR) AF: 0.213 AC: 3263 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 970 AN: 3468

East Asian (EAS) AF: 0.0875 AC: 454 AN: 5188

South Asian (SAS) AF: 0.190 AC: 915 AN: 4814

European-Finnish (FIN) AF: 0.250 AC: 2632 AN: 10546

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17531 AN: 67986

Other (OTH) AF: 0.263 AC: 556 AN: 2116

Alfa AF: 0.123 Hom.: 205

Bravo AF: 0.234

Asia WGS AF: 0.219 AC: 761 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.33
PhyloP100		0.0010
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs12204461;

hg19: chr6-149701535;

COSMIC: COSV53851699;

COSMIC: COSV53851699;