3-195867623-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R892C) has been classified as Uncertain significance.

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

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

infantile-onset mesial temporal lobe epilepsy with severe cognitive regression
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TNK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK2	NM_001382273.1 link	c.2675G>A	p.Arg892His	missense_variant	Exon 13 of 16	ENST00000672887.2	NP_001369202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNK2	ENST00000672887.2 link	c.2675G>A	p.Arg892His	missense_variant	Exon 13 of 16		NM_001382273.1	ENSP00000499899.1

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

GnomAD2 exomes

AF:

0.0139

AC:

3239

AN:

232512

AF XY:

0.0144

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 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

African (AFR)

AF:

0.00290

AC:

AN:

33440

American (AMR)

AF:

0.00460

AC:

205

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.00615

AC:

160

AN:

26010

East Asian (EAS)

AF:

0.0310

AC:

1228

AN:

39676

South Asian (SAS)

AF:

0.0168

AC:

1450

AN:

86120

European-Finnish (FIN)

AF:

0.00881

AC:

354

AN:

40190

Middle Eastern (MID)

AF:

0.0122

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0192

AC:

21290

AN:

1111256

Other (OTH)

AF:

0.0160

AC:

964

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1607

3214

4820

6427

8034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

840

1680

2520

3360

4200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0116

AC:

1762

AN:

152204

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

812

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00287

AC:

119

AN:

41524

American (AMR)

AF:

0.00915

AC:

140

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.0256

AC:

132

AN:

5162

South Asian (SAS)

AF:

0.0151

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00556

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0173

AC:

1176

AN:

67986

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

178

266

355

444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TNK2: BP4, BS1, BS2 -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Parkinson disease

Pathogenic:1

Jan 01, 2016

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

0.81

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

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over