rs56260729

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.2219C>T(p.Pro740Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,607,368 control chromosomes in the GnomAD database, including 37,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2592 hom., cov: 32)

Exomes 𝑓: 0.21 ( 35158 hom. )

Consequence

TNK2
NM_001382273.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.16

Publications

20 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=0.004432291).

BP6

Variant 3-195868079-G-A is Benign according to our data. Variant chr3-195868079-G-A is described in ClinVar as Benign. ClinVar VariationId is 259876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 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.2219C>T	p.Pro740Leu	missense	Exon 13 of 16	NP_001369202.1	A0A5F9ZGX5
TNK2	NM_001387707.1		c.2315C>T	p.Pro772Leu	missense	Exon 13 of 16	NP_001374636.1
TNK2	NM_001382272.1		c.2291C>T	p.Pro764Leu	missense	Exon 13 of 16	NP_001369201.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNK2	ENST00000672887.2	MANE Select	c.2219C>T	p.Pro740Leu	missense	Exon 13 of 16	ENSP00000499899.1	A0A5F9ZGX5
TNK2	ENST00000428187.7	TSL:1	c.2270C>T	p.Pro757Leu	missense	Exon 12 of 14	ENSP00000392546.1	C9J1X3
TNK2	ENST00000333602.14	TSL:1	c.2174C>T	p.Pro725Leu	missense	Exon 12 of 15	ENSP00000329425.6	Q07912-1

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24967

AN:

151938

Hom.:

2592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0422

Gnomad AMI

AF:

0.201

Gnomad AMR

AF:

0.186

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.0419

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.225

Gnomad OTH

AF:

0.171

GnomAD2 exomes

AF:

0.193

AC:

44352

AN:

230208

AF XY:

0.194

show subpopulations

Gnomad AFR exome

AF:

0.0411

Gnomad AMR exome

AF:

0.206

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.0403

Gnomad FIN exome

AF:

0.257

Gnomad NFE exome

AF:

0.227

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.213

AC:

310172

AN:

1455312

Hom.:

35158

Cov.:

AF XY:

0.211

AC XY:

152927

AN XY:

723774

show subpopulations

African (AFR)

AF:

0.0353

AC:

1180

AN:

33416

American (AMR)

AF:

0.205

AC:

9055

AN:

44148

Ashkenazi Jewish (ASJ)

AF:

0.276

AC:

7171

AN:

26002

East Asian (EAS)

AF:

0.0351

AC:

1389

AN:

39546

South Asian (SAS)

AF:

0.146

AC:

12550

AN:

85820

European-Finnish (FIN)

AF:

0.253

AC:

12739

AN:

50340

Middle Eastern (MID)

AF:

0.156

AC:

900

AN:

5754

European-Non Finnish (NFE)

AF:

0.228

AC:

252599

AN:

1110162

Other (OTH)

AF:

0.209

AC:

12589

AN:

60124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

15199

30397

45596

60794

75993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8520

17040

25560

34080

42600

<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:

0.164

AC:

24979

AN:

152056

Hom.:

2592

Cov.:

AF XY:

0.166

AC XY:

12316

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0421

AC:

1746

AN:

41516

American (AMR)

AF:

0.186

AC:

2846

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

942

AN:

3468

East Asian (EAS)

AF:

0.0418

AC:

216

AN:

5162

South Asian (SAS)

AF:

0.141

AC:

680

AN:

4824

European-Finnish (FIN)

AF:

0.251

AC:

2662

AN:

10590

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.225

AC:

15304

AN:

67888

Other (OTH)

AF:

0.172

AC:

364

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1027

2054

3082

4109

5136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.199

Hom.:

9698

Bravo

AF:

0.155

TwinsUK

AF:

0.243

AC:

901

ALSPAC

AF:

0.231

AC:

891

ESP6500AA

AF:

0.0435

AC:

187

ESP6500EA

AF:

0.212

AC:

1796

ExAC

AF:

0.183

AC:

21906

Asia WGS

AF:

0.117

AC:

405

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.6

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.0024

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.9

PhyloP100

1.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.92

REVEL

Benign

0.056

Sift

Benign

0.67

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.11

MPC

0.0063

ClinPred

0.00077

GERP RS

1.4

Varity_R

0.015

gMVP

0.12

Mutation Taster

=99/1

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

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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