chr16-29978095-G-A

Position:

• chr16-29978095-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_016151.4(TAOK2):​c.139G>A​(p.Asp47Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TAOK2 NM_016151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.19

Genes affected

TAOK2 (HGNC:16835): (TAO kinase 2) Enables mitogen-activated protein kinase kinase binding activity; neuropilin binding activity; and protein serine/threonine kinase activity. Involved in several processes, including focal adhesion assembly; intracellular signal transduction; and positive regulation of JNK cascade. Located in cytoplasmic vesicle; cytosol; and nuclear lumen. Part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TAOK2. . Gene score misZ 3.2101 (greater than the threshold 3.09). Trascript score misZ 3.3599 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder, immunodeficiency disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27489567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAOK2	NM_016151.4	c.139G>A	p.Asp47Asn	missense_variant	3/16	ENST00000308893.9	NP_057235.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAOK2	ENST00000308893.9	c.139G>A	p.Asp47Asn	missense_variant	3/16	1	NM_016151.4	ENSP00000310094.4
TAOK2	ENST00000543033.5	c.139G>A	p.Asp47Asn	missense_variant	3/17	1		ENSP00000440336.1
TAOK2	ENST00000279394.7	c.139G>A	p.Asp47Asn	missense_variant	3/19	1		ENSP00000279394.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 47 of the TAOK2 protein (p.Asp47Asn). This variant has not been reported in the literature in individuals affected with TAOK2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.24	N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.096
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.29	B;.;B
Vest4		0.37
MutPred		0.60		Gain of MoRF binding (P = 0.0381);Gain of MoRF binding (P = 0.0381);Gain of MoRF binding (P = 0.0381);
MVP		0.71
MPC		1.3
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs1306051542; hg19: chr16-29989416;