3-195867585-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001382273.1(TNK2):c.2713G>A(p.Val905Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,587,350 control chromosomes in the GnomAD database, including 77 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V905L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 77 hom. )

Consequence

TNK2
NM_001382273.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.866

Publications

6 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059280396).

BP6

Variant 3-195867585-C-T is Benign according to our data. Variant chr3-195867585-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 77 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK2	NM_001382273.1 link	c.2713G>A	p.Val905Met	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.2713G>A	p.Val905Met	missense_variant	Exon 13 of 16		NM_001382273.1	ENSP00000499899.1

Frequencies

GnomAD3 genomes

AF:

0.00533

AC:

811

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00980

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00528

AC:

1144

AN:

216672

AF XY:

0.00505

show subpopulations

Gnomad AFR exome

AF:

0.00233

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.000338

Gnomad EAS exome

AF:

0.0000574

Gnomad FIN exome

AF:

0.00131

Gnomad NFE exome

AF:

0.0100

Gnomad OTH exome

AF:

0.00346

GnomAD4 exome

AF:

0.00888

AC:

12749

AN:

1435162

Hom.:

Cov.:

AF XY:

0.00848

AC XY:

6053

AN XY:

713518

show subpopulations

African (AFR)

AF:

0.00157

AC:

AN:

33162

American (AMR)

AF:

0.00196

AC:

AN:

43298

Ashkenazi Jewish (ASJ)

AF:

0.000592

AC:

AN:

25348

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.000506

AC:

AN:

84948

European-Finnish (FIN)

AF:

0.00178

AC:

AN:

37602

Middle Eastern (MID)

AF:

0.00144

AC:

AN:

4876

European-Non Finnish (NFE)

AF:

0.0110

AC:

12152

AN:

1106682

Other (OTH)

AF:

0.00549

AC:

328

AN:

59692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

722

1444

2167

2889

3611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.00533

AC:

811

AN:

152188

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41526

American (AMR)

AF:

0.00124

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00980

AC:

666

AN:

67964

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00145

Hom.:

Bravo

AF:

0.00544

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00232

AC:

ESP6500EA

AF:

0.00852

AC:

ExAC

AF:

0.00537

AC:

642

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;.;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.048

LIST_S2

Uncertain

0.91

.;D;D;D

MetaRNN

Benign

0.0059

T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.69

.;.;N;.

PhyloP100

0.87

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.56

N;N;N;N

REVEL

Benign

0.046

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Benign

0.24

T;D;T;T

Polyphen

0.14, 0.21

.;B;B;B

Vest4

0.40, 0.36, 0.35

MVP

0.84

MPC

0.0066

ClinPred

0.011

GERP RS

4.7

Varity_R

0.058

gMVP

0.51

Mutation Taster

=99/1

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