NM_001382273.1:c.84T>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001382273.1(TNK2):​c.84T>G​(p.Asp28Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D28D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TNK2 NM_001382273.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK2	NM_001382273.1	c.84T>G	p.Asp28Glu	missense_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>G	p.Asp28Glu	missense_variant	Exon 2 of 16		NM_001382273.1	ENSP00000499899.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 34098

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	8.7
DANN	Benign	0.97
DEOGEN2	Benign	0.39	.;T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.90	D;D;D;.;.
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.7	.;L;.;.;.
PhyloP100		-0.79
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.44
Sift	Benign	0.077	T;T;T;T;T
Sift4G	Benign	0.15	T;D;T;.;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.59
MutPred		0.41		.;.;Gain of helix (P = 0.0325);.;.;
MVP		0.60
MPC		1.2
ClinPred		0.90	D
GERP RS		-6.0
PromoterAI		-0.12	Neutral
Varity_R		0.37
gMVP		0.79
Mutation Taster		=47/53	disease causing

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;