Genetic Variant TNK2:p.Arg972Gly (chr3-195867384-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001382273.1(TNK2):c.2914C>G(p.Arg972Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TNK2
NM_001382273.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.54

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29300427).

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.2914C>G	p.Arg972Gly	missense	Exon 13 of 16	NP_001369202.1	A0A5F9ZGX5
TNK2	NM_001387707.1		c.3010C>G	p.Arg1004Gly	missense	Exon 13 of 16	NP_001374636.1
TNK2	NM_001382272.1		c.2986C>G	p.Arg996Gly	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.2914C>G	p.Arg972Gly	missense	Exon 13 of 16	ENSP00000499899.1	A0A5F9ZGX5
TNK2	ENST00000428187.7	TSL:1	c.2965C>G	p.Arg989Gly	missense	Exon 12 of 14	ENSP00000392546.1	C9J1X3
TNK2	ENST00000333602.14	TSL:1	c.2869C>G	p.Arg957Gly	missense	Exon 12 of 15	ENSP00000329425.6	Q07912-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452558

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.00

AC:

AN:

43744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25890

East Asian (EAS)

AF:

0.00

AC:

AN:

39476

South Asian (SAS)

AF:

0.00

AC:

AN:

85566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109532

Other (OTH)

AF:

0.00

AC:

AN:

60008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.015

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.9

PhyloP100

3.5

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.87

REVEL

Benign

0.24

Sift

Benign

0.031

Sift4G

Benign

0.078

Polyphen

0.60

Vest4

0.70

MutPred

0.20

Gain of catalytic residue at P985 (P = 0.0702)

MVP

0.83

MPC

0.0077

ClinPred

0.37

GERP RS

4.9

Varity_R

0.11

gMVP

0.52

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over