rs148323328

Variant names:

• chr3-195867585-C-A
• rs148323328
• NM_001382273.1:c.2713G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-195867585-C-A
• chr3-195867585-C-G
• chr3-195867585-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382273.1(TNK2):​c.2713G>T​(p.Val905Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V905M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TNK2 NM_001382273.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.866
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.109303296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK2	NM_001382273.1	c.2713G>T	p.Val905Leu	missense_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.2713G>T	p.Val905Leu	missense_variant	Exon 13 of 16		NM_001382273.1	ENSP00000499899.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435170 Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0 AN XY: 713522

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 43298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 84948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37602

Middle Eastern (MID) AF: 0.000205 AC: 1 AN: 4876

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106690

Other (OTH) AF: 0.00 AC: 0 AN: 59692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.7
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T;.;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.34	.;.;N;.
PhyloP100		0.87
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.48	N;N;N;N
REVEL	Benign	0.049
Sift	Benign	0.052	T;D;D;D
Sift4G	Benign	0.98	T;T;T;T
Polyphen		0.0	.;B;B;B
Vest4		0.34, 0.31, 0.38
MutPred		0.19		.;.;.;Gain of glycosylation at P921 (P = 0.0574);
MVP		0.82
MPC		0.0066
ClinPred		0.034	T
GERP RS		4.7
Varity_R		0.079
gMVP		0.50
Mutation Taster		=96/4	polymorphism

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: rs148323328; hg19: chr3-195594456;