chr3-195867934-A-G

Variant names:

• chr3-195867934-A-G
• rs1056749
• NM_001382273.1:c.2364T>C

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.2364T>C​(p.Ala788Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,532,962 control chromosomes in the GnomAD database, including 22,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1885 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20335 hom.)
• Consequence: TNK2 NM_001382273.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.277
• Publications: 14 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 3-195867934-A-G is Benign according to our data. Variant chr3-195867934-A-G is described in ClinVar as Benign. ClinVar VariationId is 259877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.277 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK2	NM_001382273.1	c.2364T>C	p.Ala788Ala	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.2364T>C	p.Ala788Ala	synonymous_variant	Exon 13 of 16		NM_001382273.1	ENSP00000499899.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23190 AN: 151564 Hom.: 1887 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0448

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.143 AC: 22033 AN: 154566 AF XY: 0.145

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0787

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.0504

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.168 AC: 232537 AN: 1381278 Hom.: 20335 Cov.: 50 AF XY: 0.167 AC XY: 114204 AN XY: 682540

African (AFR) AF: 0.164 AC: 5012 AN: 30490

American (AMR) AF: 0.0825 AC: 2238 AN: 27124

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2451 AN: 22980

East Asian (EAS) AF: 0.0667 AC: 2558 AN: 38370

South Asian (SAS) AF: 0.127 AC: 9744 AN: 76744

European-Finnish (FIN) AF: 0.132 AC: 5269 AN: 39988

Middle Eastern (MID) AF: 0.138 AC: 757 AN: 5502

European-Non Finnish (NFE) AF: 0.180 AC: 195269 AN: 1082738

Other (OTH) AF: 0.161 AC: 9239 AN: 57342

GnomAD4 genome AF: 0.153 AC: 23184 AN: 151684 Hom.: 1885 Cov.: 32 AF XY: 0.150 AC XY: 11159 AN XY: 74148

African (AFR) AF: 0.161 AC: 6640 AN: 41350

American (AMR) AF: 0.105 AC: 1600 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 386 AN: 3466

East Asian (EAS) AF: 0.0446 AC: 226 AN: 5072

South Asian (SAS) AF: 0.122 AC: 587 AN: 4808

European-Finnish (FIN) AF: 0.126 AC: 1336 AN: 10574

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.176 AC: 11947 AN: 67844

Other (OTH) AF: 0.143 AC: 300 AN: 2102

Alfa AF: 0.160 Hom.: 460

Bravo AF: 0.152

Asia WGS AF: 0.0860 AC: 300 AN: 3478

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	6.6
DANN	Benign	0.40
PhyloP100		0.28
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: rs1056749; hg19: chr3-195594805; COSMIC: COSV57365543; COSMIC: COSV57365543;