chr3-195868341-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001382273.1(TNK2):c.1957G>A(p.Val653Met) variant causes a missense change. The variant allele was found at a frequency of 0.00174 in 1,601,154 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V653V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 24 hom. )

Consequence

TNK2
NM_001382273.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.63

Publications

14 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=0.0081579685).

BP6

Variant 3-195868341-C-T is Benign according to our data. Variant chr3-195868341-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 88849.

BS2

High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK2	NM_001382273.1 link	c.1957G>A	p.Val653Met	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.1957G>A	p.Val653Met	missense_variant	Exon 13 of 16		NM_001382273.1	ENSP00000499899.1		A0A5F9ZGX5

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

189

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00376

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.0160

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00254

AC:

591

AN:

232414

AF XY:

0.00315

show subpopulations

Gnomad AFR exome

AF:

0.000417

Gnomad AMR exome

AF:

0.000586

Gnomad ASJ exome

AF:

0.00442

Gnomad EAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.0000695

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.00180

AC:

2602

AN:

1449220

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

1519

AN XY:

721414

show subpopulations

African (AFR)

AF:

0.000420

AC:

AN:

33344

American (AMR)

AF:

0.000449

AC:

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.00415

AC:

108

AN:

26000

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39594

South Asian (SAS)

AF:

0.0127

AC:

1090

AN:

86112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42960

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00110

AC:

1227

AN:

1110764

Other (OTH)

AF:

0.00189

AC:

114

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

162

324

487

649

811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00124

AC:

188

AN:

151934

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41446

American (AMR)

AF:

0.000524

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00376

AC:

AN:

3462

East Asian (EAS)

AF:

0.000391

AC:

AN:

5120

South Asian (SAS)

AF:

0.0158

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00133

Hom.:

Bravo

AF:

0.000839

ESP6500AA

AF:

0.000234

AC:

ESP6500EA

AF:

0.000824

AC:

ExAC

AF:

0.00244

AC:

293

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Parkinson disease

Uncertain:1

Jan 01, 2016

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Autosomal recessive infantile epilepsy

Uncertain:1

Sep 01, 2013

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

TNK2-related disorder

Benign:1

Nov 15, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Infantile epilepsy

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Val716Met variant in TNK2 has been identified in 3 Belgian and Italian siblings from 1 family with infantile-onset epilepsy (PMID: 23686771), and has been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Furthermore, this is the first report of pathogenicity for a variant in this gene. In vitro functional studies provide some evidence that the p.Val716Met variant may slightly impact protein function (PMID: 23686771). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive infantile-onset epilepsy. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

T;.;T;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D

MetaRNN

Benign

0.0082

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.8

.;.;L;.

PhyloP100

4.6

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.0080

D;D;D;D

Sift4G

Benign

0.073

T;D;T;D

Polyphen

1.0

.;D;D;D

Vest4

0.63, 0.69, 0.66

MVP

0.85

MPC

0.034

ClinPred

0.024

GERP RS

5.5

Varity_R

0.32

gMVP

0.35

Mutation Taster

=95/5

polymorphism

(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