3-195867623-C-G

Variant names:

• chr3-195867623-C-G
• rs112384084
• NM_001382273.1:c.2675G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001382273.1(TNK2):​c.2675G>C​(p.Arg892Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R892H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNK2 NM_001382273.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.806
• 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
• genetic generalized epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28376287).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382273.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNK2	NM_001382273.1	MANE Select	c.2675G>C	p.Arg892Pro	missense	Exon 13 of 16	NP_001369202.1	A0A5F9ZGX5
	TNK2	NM_001387707.1		c.2771G>C	p.Arg924Pro	missense	Exon 13 of 16	NP_001374636.1
	TNK2	NM_001382272.1		c.2747G>C	p.Arg916Pro	missense	Exon 13 of 16	NP_001369201.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNK2	ENST00000672887.2	MANE Select	c.2675G>C	p.Arg892Pro	missense	Exon 13 of 16	ENSP00000499899.1	A0A5F9ZGX5
	TNK2	ENST00000428187.7	TSL:1	c.2726G>C	p.Arg909Pro	missense	Exon 12 of 14	ENSP00000392546.1	C9J1X3
	TNK2	ENST00000333602.14	TSL:1	c.2630G>C	p.Arg877Pro	missense	Exon 12 of 15	ENSP00000329425.6	Q07912-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447190 Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0 AN XY: 720220

⚠️ 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: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111264

Other (OTH) AF: 0.00 AC: 0 AN: 60220

⚠️ 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.81
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.20	B
Vest4		0.50
MutPred		0.20		Gain of glycosylation at R909 (P = 0.0338)
MVP		0.89
MPC		0.017
ClinPred		0.96	D
GERP RS		0.17
Varity_R		0.41
gMVP		0.55
Mutation Taster		=92/8	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: rs112384084; hg19: chr3-195594494;