6-149370079-G-A

Variant names:

• chr6-149370079-G-A
• NM_001292034.3:c.82G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001292034.3(TAB2):​c.82G>A​(p.Val28Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TAB2 NM_001292034.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52
• 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, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• polyvalvular heart disease syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

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.82G>A	p.Val28Ile	missense	Exon 2 of 7	NP_001278963.1	Q9NYJ8-1
	TAB2	NM_001369506.1		c.82G>A	p.Val28Ile	missense	Exon 3 of 8	NP_001356435.1	Q9NYJ8-1
	TAB2	NM_015093.6		c.82G>A	p.Val28Ile	missense	Exon 4 of 9	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.82G>A	p.Val28Ile	missense	Exon 2 of 7	ENSP00000490618.1	Q9NYJ8-1
	TAB2	ENST00000470466.5	TSL:1	n.82G>A		non_coding_transcript_exon	Exon 2 of 8	ENSP00000432709.1	Q9NYJ8-2
	TAB2	ENST00000367456.5	TSL:5	c.82G>A	p.Val28Ile	missense	Exon 3 of 8	ENSP00000356426.1	Q9NYJ8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.54		Gain of catalytic residue at L33 (P = 0.0547)
MVP		0.78
MPC		0.94
ClinPred		0.85	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.53
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr6-149691215;