rs56260729

Positions:

• chr3-195868079-G-A
• chr3-195868079-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNK2	NM_001382273.1	c.2219C>T	p.Pro740Leu	missense_variant	13/16	ENST00000672887.2	NP_001369202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNK2	ENST00000672887.2	c.2219C>T	p.Pro740Leu	missense_variant	13/16		NM_001382273.1	ENSP00000499899

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24967 AN: 151938 Hom.: 2592 Cov.: 32

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

GnomAD3 exomes AF: 0.193 AC: 44352 AN: 230208 Hom.: 4791 AF XY: 0.194 AC XY: 24642 AN XY: 126890

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 SAS exome AF: 0.150

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.: 64 AF XY: 0.211 AC XY: 152927 AN XY: 723774

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.0351

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.164 AC: 24979 AN: 152056 Hom.: 2592 Cov.: 32 AF XY: 0.166 AC XY: 12316 AN XY: 74334

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.0418

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.251

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.172

Alfa AF: 0.203 Hom.: 3446

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.6
DANN	Benign	0.57
DEOGEN2	Benign	0.0024	T;.;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.63	.;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.9	.;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.92	N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.67	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.0	.;B;B;B
Vest4		0.11, 0.14, 0.090
MPC		0.0063
ClinPred		0.00077	T
GERP RS		1.4
Varity_R		0.015
gMVP		0.12

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

Other links and lift over

dbSNP: rs56260729; hg19: chr3-195594950;