Variant 3-195867383-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001382273.1(TNK2):c.2915G>A(p.Arg972Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000517 in 1,604,232 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R972W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 1 hom. )

Consequence

TNK2
NM_001382273.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.829

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10268214).

BS2

High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNK2	NM_001382273.1 linkuse as main transcript	c.2915G>A	p.Arg972Gln	missense_variant	13/16	ENST00000672887.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNK2	ENST00000672887.2 linkuse as main transcript	c.2915G>A	p.Arg972Gln	missense_variant	13/16		NM_001382273.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

221874

Hom.:

AF XY:

0.0000327

AC XY:

AN XY:

122234

show subpopulations

Gnomad AFR exome

AF:

0.000302

Gnomad AMR exome

AF:

0.0000305

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000678

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000718

Gnomad OTH exome

AF:

0.000183

GnomAD4 exome

AF:

0.0000503

AC:

AN:

1451892

Hom.:

Cov.:

AF XY:

0.0000429

AC XY:

AN XY:

722048

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.0000458

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000433

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.000461

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000918

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2022

The c.3104G>A (p.R1035Q) alteration is located in exon 13 (coding exon 13) of the TNK2 gene. This alteration results from a G to A substitution at nucleotide position 3104, causing the arginine (R) at amino acid position 1035 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.0093

T;.;T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.51

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.83

MutationTaster

Benign

0.98

N;N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.58

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.098, 0.36, 0.024

.;B;B;B

Vest4

0.41, 0.43, 0.42

MVP

0.88

MPC

0.0061

ClinPred

0.014

GERP RS

4.0

Varity_R

0.056

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over