rs3747673

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001382273.1(TNK2):c.295C>T(p.Arg99Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00305 in 1,613,722 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 35 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 208 hom. )

Consequence

TNK2
NM_001382273.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.66

Publications

17 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
genetic generalized epilepsy
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

TNK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077377856).

BP6

Variant 3-195884973-G-A is Benign according to our data. Variant chr3-195884973-G-A is described in ClinVar as Benign. ClinVar VariationId is 707553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0963 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382273.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNK2	NM_001382273.1	MANE Select	c.295C>T	p.Arg99Trp	missense	Exon 4 of 16	NP_001369202.1	A0A5F9ZGX5
TNK2	NM_001387707.1		c.391C>T	p.Arg131Trp	missense	Exon 4 of 16	NP_001374636.1
TNK2	NM_001382272.1		c.367C>T	p.Arg123Trp	missense	Exon 4 of 16	NP_001369201.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNK2	ENST00000672887.2	MANE Select	c.295C>T	p.Arg99Trp	missense	Exon 4 of 16	ENSP00000499899.1	A0A5F9ZGX5
TNK2	ENST00000428187.7	TSL:1	c.391C>T	p.Arg131Trp	missense	Exon 4 of 14	ENSP00000392546.1	C9J1X3
TNK2	ENST00000333602.14	TSL:1	c.295C>T	p.Arg99Trp	missense	Exon 4 of 15	ENSP00000329425.6	Q07912-1

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

577

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00849

AC:

2124

AN:

250090

AF XY:

0.00775

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00298

AC:

4350

AN:

1461462

Hom.:

208

Cov.:

AF XY:

0.00286

AC XY:

2080

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33456

American (AMR)

AF:

0.000112

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26092

East Asian (EAS)

AF:

0.0964

AC:

3825

AN:

39690

South Asian (SAS)

AF:

0.00245

AC:

211

AN:

86216

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000131

AC:

146

AN:

1111828

Other (OTH)

AF:

0.00239

AC:

144

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

249

499

748

998

1247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00380

AC:

578

AN:

152260

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

343

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41576

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.104

AC:

533

AN:

5148

South Asian (SAS)

AF:

0.00415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68004

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00307

Hom.:

Bravo

AF:

0.00546

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00827

AC:

1004

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.099

Eigen_PC

Benign

0.013

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.5

PhyloP100

5.7

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

0.083

Vest4

0.68

MVP

0.92

MPC

1.2

ClinPred

0.076

GERP RS

3.0

Varity_R

0.19

gMVP

0.48

Mutation Taster

=90/10

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over