6-149397705-GAA-AAG

Variant names:

• chr6-149397705-GAA-AAG
• NM_001292034.3:c.1705_1707delGAAinsAAG
• TAB2 p.Glu569Lys

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001292034.3(TAB2):​c.1705_1707delGAAinsAAG​(p.Glu569Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAB2 NM_001292034.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.38
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1705_1707delGAAinsAAG	p.Glu569Lys	missense	N/A	NP_001278963.1	Q9NYJ8-1
	TAB2	NM_001369506.1		c.1705_1707delGAAinsAAG	p.Glu569Lys	missense	N/A	NP_001356435.1	Q9NYJ8-1
	TAB2	NM_015093.6		c.1705_1707delGAAinsAAG	p.Glu569Lys	missense	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.1705_1707delGAAinsAAG	p.Glu569Lys	missense	N/A	ENSP00000490618.1	Q9NYJ8-1
	TAB2	ENST00000470466.5	TSL:1	n.*304_*306delGAAinsAAG		non_coding_transcript_exon	Exon 5 of 8	ENSP00000432709.1	Q9NYJ8-2
	TAB2	ENST00000470466.5	TSL:1	n.*304_*306delGAAinsAAG		3_prime_UTR	Exon 5 of 8	ENSP00000432709.1	Q9NYJ8-2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

Splicing

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

hg19: chr6-149718841;