3-195864185-C-T

Position:

• chr3-195864185-C-T

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.3164G>A​(p.Arg1055His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,613,758 control chromosomes in the GnomAD database, including 1,831 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (122 hom., cov: 31)
  • Exomes 𝑓: 0.045 (1709 hom.)
• Consequence: TNK2 NM_001382273.1 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.48

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=0.0051119924).
• BP6: Variant 3-195864185-C-T is Benign according to our data. Variant chr3-195864185-C-T is described in ClinVar as [Benign]. Clinvar id is 259879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-195864185-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNK2	NM_001382273.1	c.3164G>A	p.Arg1055His	missense_variant, splice_region_variant	16/16	ENST00000672887.2	NP_001369202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNK2	ENST00000672887.2	c.3164G>A	p.Arg1055His	missense_variant, splice_region_variant	16/16		NM_001382273.1	ENSP00000499899

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 5215 AN: 152060 Hom.: 122 Cov.: 31

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0465

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0321 AC: 7981 AN: 248970 Hom.: 181 AF XY: 0.0309 AC XY: 4161 AN XY: 134788

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0333

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00696

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0483

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0445 AC: 65092 AN: 1461580 Hom.: 1709 Cov.: 31 AF XY: 0.0432 AC XY: 31446 AN XY: 727108

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.0333

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00793

Gnomad4 FIN exome AF: 0.0326

Gnomad4 NFE exome AF: 0.0523

Gnomad4 OTH exome AF: 0.0362

GnomAD4 genome AF: 0.0343 AC: 5217 AN: 152178 Hom.: 122 Cov.: 31 AF XY: 0.0325 AC XY: 2420 AN XY: 74392

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0465

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0501

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0429 Hom.: 178

Bravo AF: 0.0335

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0560 AC: 216

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.0487 AC: 419

ExAC AF: 0.0314 AC: 3811

Asia WGS AF: 0.00895 AC: 32 AN: 3478

EpiCase AF: 0.0412

EpiControl AF: 0.0417

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.013	T;.;T;T
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	.;D;D;D
MetaRNN	Benign	0.0051	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.4	.;.;L;.
MutationTaster	Benign	0.86	N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.35, 0.24	.;B;B;B
Vest4		0.19, 0.23, 0.14
MPC		0.029
ClinPred		0.025	T
GERP RS		3.8
Varity_R		0.091
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs13433937; hg19: chr3-195591056;