chr3-195868183-C-T

Variant names:

• chr3-195868183-C-T
• rs7516
• NM_001382273.1:c.2115G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001382273.1(TNK2):​c.2115G>A​(p.Pro705Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,608,866 control chromosomes in the GnomAD database, including 11,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (910 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10735 hom.)
• Consequence: TNK2 NM_001382273.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.949
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-195868183-C-T is Benign according to our data. Variant chr3-195868183-C-T is described in ClinVar as Benign. ClinVar VariationId is 259873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.949 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK2	NM_001382273.1	c.2115G>A	p.Pro705Pro	synonymous_variant	Exon 13 of 16	ENST00000672887.2	NP_001369202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNK2	ENST00000672887.2	c.2115G>A	p.Pro705Pro	synonymous_variant	Exon 13 of 16		NM_001382273.1	ENSP00000499899.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16065 AN: 151924 Hom.: 911 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0715

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.0387

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0895

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0988

GnomAD2 exomes AF: 0.103 AC: 24009 AN: 233702 AF XY: 0.107

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0499

Gnomad ASJ exome AF: 0.0906

Gnomad EAS exome AF: 0.0435

Gnomad FIN exome AF: 0.0928

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.118 AC: 172199 AN: 1456824 Hom.: 10735 Cov.: 54 AF XY: 0.119 AC XY: 86064 AN XY: 724696

African (AFR) AF: 0.105 AC: 3500 AN: 33414

American (AMR) AF: 0.0531 AC: 2351 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.0892 AC: 2318 AN: 25990

East Asian (EAS) AF: 0.0537 AC: 2126 AN: 39626

South Asian (SAS) AF: 0.124 AC: 10620 AN: 85984

European-Finnish (FIN) AF: 0.0947 AC: 4844 AN: 51142

Middle Eastern (MID) AF: 0.126 AC: 723 AN: 5760

European-Non Finnish (NFE) AF: 0.125 AC: 139004 AN: 1110442

Other (OTH) AF: 0.112 AC: 6713 AN: 60164

GnomAD4 genome AF: 0.106 AC: 16061 AN: 152042 Hom.: 910 Cov.: 33 AF XY: 0.104 AC XY: 7693 AN XY: 74318

African (AFR) AF: 0.102 AC: 4249 AN: 41478

American (AMR) AF: 0.0714 AC: 1093 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 303 AN: 3470

East Asian (EAS) AF: 0.0386 AC: 199 AN: 5150

South Asian (SAS) AF: 0.115 AC: 554 AN: 4826

European-Finnish (FIN) AF: 0.0895 AC: 948 AN: 10596

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8358 AN: 67906

Other (OTH) AF: 0.0977 AC: 206 AN: 2108

Alfa AF: 0.117 Hom.: 428

Bravo AF: 0.104

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.084
DANN	Benign	0.54
PhyloP100		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7516; hg19: chr3-195595054; COSMIC: COSV57369831; COSMIC: COSV57369831;