3-195867384-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001382273.1(TNK2):c.2914C>T(p.Arg972Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,604,782 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R972Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: TNK2 NM_001382273.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54

Genes affected

TNK2 (HGNC:19297): (tyrosine kinase non receptor 2) This gene encodes a tyrosine kinase that binds Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42235863).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNK2	NM_001382273.1	c.2914C>T	p.Arg972Trp	missense_variant	13/16	ENST00000672887.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNK2	ENST00000672887.2	c.2914C>T	p.Arg972Trp	missense_variant	13/16		NM_001382273.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000179 AC: 4 AN: 223516 Hom.: 0 AF XY: 0.0000244 AC XY: 3 AN XY: 123000

Gnomad AFR exome AF: 0.0000750

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000203

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000324 AC: 47 AN: 1452558 Hom.: 0 Cov.: 38 AF XY: 0.0000263 AC XY: 19 AN XY: 722392

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000361

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000417 AC: 5

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

Invitae

Jan 06, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1035 of the TNK2 protein (p.Arg1035Trp). This variant is present in population databases (rs748112786, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with TNK2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.028	T;.;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	0.87	N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N;N;D;N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;T
Polyphen		1.0, 0.98, 0.99	.;D;D;D
Vest4		0.68, 0.61, 0.69
MutPred		0.21		.;.;.;Loss of disorder (P = 0.0301);
MVP		0.92
MPC		0.019
ClinPred		0.46	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748112786; hg19: chr3-195594255;