3-195888505-A-G

Variant names:

• chr3-195888505-A-G
• rs3747669
• NM_001382273.1:c.84T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BA1

The NM_001382273.1(TNK2):​c.84T>C​(p.Asp28Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,612,956 control chromosomes in the GnomAD database, including 79,118 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12905 hom., cov: 30)
  • Exomes 𝑓: 0.29 (66213 hom.)
• Consequence: TNK2 NM_001382273.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.789
• Publications: 23 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 -17 ACMG points.

• BP6: Variant 3-195888505-A-G is Benign according to our data. Variant chr3-195888505-A-G is described in ClinVar as Benign. ClinVar VariationId is 259882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.789 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK2	NM_001382273.1	c.84T>C	p.Asp28Asp	synonymous_variant	Exon 2 of 16	ENST00000672887.2	NP_001369202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNK2	ENST00000672887.2	c.84T>C	p.Asp28Asp	synonymous_variant	Exon 2 of 16		NM_001382273.1	ENSP00000499899.1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58818 AN: 151702 Hom.: 12883 Cov.: 30

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.337 AC: 84585 AN: 250728 AF XY: 0.329

Gnomad AFR exome AF: 0.611

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.294 AC: 428921 AN: 1461136 Hom.: 66213 Cov.: 36 AF XY: 0.292 AC XY: 212434 AN XY: 726840

African (AFR) AF: 0.608 AC: 20343 AN: 33450

American (AMR) AF: 0.391 AC: 17456 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 10789 AN: 26112

East Asian (EAS) AF: 0.428 AC: 16967 AN: 39664

South Asian (SAS) AF: 0.302 AC: 25992 AN: 86200

European-Finnish (FIN) AF: 0.293 AC: 15625 AN: 53378

Middle Eastern (MID) AF: 0.415 AC: 2305 AN: 5558

European-Non Finnish (NFE) AF: 0.270 AC: 299627 AN: 1111774

Other (OTH) AF: 0.328 AC: 19817 AN: 60344

GnomAD4 genome AF: 0.388 AC: 58893 AN: 151820 Hom.: 12905 Cov.: 30 AF XY: 0.387 AC XY: 28724 AN XY: 74174

African (AFR) AF: 0.603 AC: 24971 AN: 41396

American (AMR) AF: 0.388 AC: 5919 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1409 AN: 3472

East Asian (EAS) AF: 0.441 AC: 2278 AN: 5162

South Asian (SAS) AF: 0.303 AC: 1450 AN: 4780

European-Finnish (FIN) AF: 0.290 AC: 3047 AN: 10518

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18698 AN: 67910

Other (OTH) AF: 0.369 AC: 776 AN: 2102

Alfa AF: 0.316 Hom.: 34098

Bravo AF: 0.409

Asia WGS AF: 0.411 AC: 1428 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.297

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	-0.82
CADD	Benign	0.89
DANN	Benign	0.24
PhyloP100		-0.79
PromoterAI		-0.069	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3747669; hg19: chr3-195615376; COSMIC: COSV57376334; COSMIC: COSV57376334;