chr3-195867623-C-T

Position:

chr3-195867623-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001382273.1(TNK2):c.2675G>A(p.Arg892His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,599,384 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 15 hom., cov: 32)

Exomes 𝑓: 0.018 ( 279 hom. )

Consequence

TNK2
NM_001382273.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:3

Conservation

PhyloP100: 0.806

Variant links:

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]

TNK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003913641).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0116 (1762/152204) while in subpopulation EAS AF= 0.0256 (132/5162). AF 95% confidence interval is 0.022. There are 15 homozygotes in gnomad4. There are 812 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 1762 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNK2	NM_001382273.1 linkuse as main transcript	c.2675G>A	p.Arg892His	missense_variant	13/16	ENST00000672887.2	NP_001369202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNK2	ENST00000672887.2 linkuse as main transcript	c.2675G>A	p.Arg892His	missense_variant	13/16		NM_001382273.1	ENSP00000499899

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1765

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.00916

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.0257

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.0139

AC:

3239

AN:

232512

Hom.:

AF XY:

0.0144

AC XY:

1841

AN XY:

128004

show subpopulations

Gnomad AFR exome

AF:

0.00318

Gnomad AMR exome

AF:

0.00383

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.0259

Gnomad SAS exome

AF:

0.0166

Gnomad FIN exome

AF:

0.00769

Gnomad NFE exome

AF:

0.0174

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.0178

AC:

25818

AN:

1447180

Hom.:

279

Cov.:

AF XY:

0.0176

AC XY:

12669

AN XY:

720216

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.00460

Gnomad4 ASJ exome

AF:

0.00615

Gnomad4 EAS exome

AF:

0.0310

Gnomad4 SAS exome

AF:

0.0168

Gnomad4 FIN exome

AF:

0.00881

Gnomad4 NFE exome

AF:

0.0192

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0116

AC:

1762

AN:

152204

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

812

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00287

Gnomad4 AMR

AF:

0.00915

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.0256

Gnomad4 SAS

AF:

0.0151

Gnomad4 FIN

AF:

0.00556

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0116

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.0175

AC:

150

ExAC

AF:

0.0143

AC:

1728

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TNK2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Parkinson disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jan 01, 2016

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.81

.;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

.;.;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.7

D;N;N;N

REVEL

Benign

0.068

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Uncertain

0.011

D;T;T;T

Polyphen

0.0010, 0.81, 0.43

.;B;P;B

Vest4

0.32, 0.23, 0.29

MPC

0.0061

ClinPred

0.023

GERP RS

0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over