rs112384084

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-195867623-C-T
• chr3-195867623-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001382273.1(TNK2):​c.2675G>A​(p.Arg892His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,599,384 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R892C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 32)
  • Exomes 𝑓: 0.018 (279 hom.)
• Consequence: TNK2 NM_001382273.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:3
• Conservation: PhyloP100: 0.806
• Publications: 15 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003913641).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0116 (1762/152204) while in subpopulation EAS AF = 0.0256 (132/5162). AF 95% confidence interval is 0.022. There are 15 homozygotes in GnomAd4. There are 812 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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>A	p.Arg892His	missense	Exon 13 of 16	NP_001369202.1	A0A5F9ZGX5
	TNK2	NM_001387707.1		c.2771G>A	p.Arg924His	missense	Exon 13 of 16	NP_001374636.1
	TNK2	NM_001382272.1		c.2747G>A	p.Arg916His	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>A	p.Arg892His	missense	Exon 13 of 16	ENSP00000499899.1	A0A5F9ZGX5
	TNK2	ENST00000428187.7	TSL:1	c.2726G>A	p.Arg909His	missense	Exon 12 of 14	ENSP00000392546.1	C9J1X3
	TNK2	ENST00000333602.14	TSL:1	c.2630G>A	p.Arg877His	missense	Exon 12 of 15	ENSP00000329425.6	Q07912-1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1765 AN: 152086 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0257

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0139 AC: 3239 AN: 232512 AF XY: 0.0144

Gnomad AFR exome AF: 0.00318

Gnomad AMR exome AF: 0.00383

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.0259

Gnomad FIN exome AF: 0.00769

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0178 AC: 25818 AN: 1447180 Hom.: 279 Cov.: 52 AF XY: 0.0176 AC XY: 12669 AN XY: 720216

African (AFR) AF: 0.00290 AC: 97 AN: 33440

American (AMR) AF: 0.00460 AC: 205 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00615 AC: 160 AN: 26010

East Asian (EAS) AF: 0.0310 AC: 1228 AN: 39676

South Asian (SAS) AF: 0.0168 AC: 1450 AN: 86120

European-Finnish (FIN) AF: 0.00881 AC: 354 AN: 40190

Middle Eastern (MID) AF: 0.0122 AC: 70 AN: 5718

European-Non Finnish (NFE) AF: 0.0192 AC: 21290 AN: 1111256

Other (OTH) AF: 0.0160 AC: 964 AN: 60220

GnomAD4 genome AF: 0.0116 AC: 1762 AN: 152204 Hom.: 15 Cov.: 32 AF XY: 0.0109 AC XY: 812 AN XY: 74406

African (AFR) AF: 0.00287 AC: 119 AN: 41524

American (AMR) AF: 0.00915 AC: 140 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.0256 AC: 132 AN: 5162

South Asian (SAS) AF: 0.0151 AC: 73 AN: 4826

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1176 AN: 67986

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0154 Hom.: 65

Bravo AF: 0.0116

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.0175 AC: 150

ExAC AF: 0.0143 AC: 1728

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
1	-	-	Parkinson disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.81
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.068
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.011	D
Polyphen		0.0010	B
Vest4		0.32
MPC		0.0061
ClinPred		0.023	T
GERP RS		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.30
Mutation Taster		=100/0	disease causing (ClinVar)

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; COSMIC: COSV57369804; COSMIC: COSV57369804;