3-195867370-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001382273.1(TNK2):c.2928G>C(p.Lys976Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,606,930 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (9 hom.)
• Consequence: TNK2 NM_001382273.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.14

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005574286).
• BP6: Variant 3-195867370-C-G is Benign according to our data. Variant chr3-195867370-C-G is described in ClinVar as [Benign]. Clinvar id is 1588853.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-195867370-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00571 (870/152330) while in subpopulation AFR AF= 0.02 (830/41570). AF 95% confidence interval is 0.0188. There are 11 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 867 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNK2	NM_001382273.1	c.2928G>C	p.Lys976Asn	missense_variant	13/16	ENST00000672887.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNK2	ENST00000672887.2	c.2928G>C	p.Lys976Asn	missense_variant	13/16		NM_001382273.1

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 867 AN: 152214 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00130 AC: 295 AN: 227262 Hom.: 5 AF XY: 0.000993 AC XY: 124 AN XY: 124906

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.000604 AC: 879 AN: 1454600 Hom.: 9 Cov.: 38 AF XY: 0.000503 AC XY: 364 AN XY: 723402

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.000797

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.00571 AC: 870 AN: 152330 Hom.: 11 Cov.: 33 AF XY: 0.00575 AC XY: 428 AN XY: 74498

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00163 Hom.: 1

Bravo AF: 0.00632

ESP6500AA AF: 0.0167 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00144 AC: 173

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.033	T;.;T;T
Eigen	Benign	0.011
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	0.70	N;N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.076
Sift	Uncertain	0.022	D;D;T;D
Sift4G	Uncertain	0.028	D;T;T;T
Polyphen		1.0, 0.047, 0.98	.;D;B;D
Vest4		0.61, 0.64, 0.60
MutPred		0.25		.;.;.;Loss of methylation at K993 (P = 0.0063);
MVP		0.84
MPC		0.0083
ClinPred		0.0077	T
GERP RS		4.9
Varity_R		0.19
gMVP		0.58

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: rs201293924; hg19: chr3-195594241;