chr3-195867585-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001382273.1(TNK2):​c.2713G>A​(p.Val905Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,587,350 control chromosomes in the GnomAD database, including 77 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V905L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (77 hom.)
• Consequence: TNK2 NM_001382273.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.866
• Publications: 6 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059280396).
• BP6: Variant 3-195867585-C-T is Benign according to our data. Variant chr3-195867585-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 77 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNK2	NM_001382273.1	MANE Select	c.2713G>A	p.Val905Met	missense	Exon 13 of 16	NP_001369202.1
	TNK2	NM_001387707.1		c.2809G>A	p.Val937Met	missense	Exon 13 of 16	NP_001374636.1
	TNK2	NM_001382272.1		c.2785G>A	p.Val929Met	missense	Exon 13 of 16	NP_001369201.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNK2	ENST00000672887.2	MANE Select	c.2713G>A	p.Val905Met	missense	Exon 13 of 16	ENSP00000499899.1
	TNK2	ENST00000428187.7	TSL:1	c.2764G>A	p.Val922Met	missense	Exon 12 of 14	ENSP00000392546.1
	TNK2	ENST00000333602.14	TSL:1	c.2668G>A	p.Val890Met	missense	Exon 12 of 15	ENSP00000329425.6

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00980

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00528 AC: 1144 AN: 216672 AF XY: 0.00505

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000338

Gnomad EAS exome AF: 0.0000574

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00888 AC: 12749 AN: 1435162 Hom.: 77 Cov.: 52 AF XY: 0.00848 AC XY: 6053 AN XY: 713518

African (AFR) AF: 0.00157 AC: 52 AN: 33162

American (AMR) AF: 0.00196 AC: 85 AN: 43298

Ashkenazi Jewish (ASJ) AF: 0.000592 AC: 15 AN: 25348

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

South Asian (SAS) AF: 0.000506 AC: 43 AN: 84948

European-Finnish (FIN) AF: 0.00178 AC: 67 AN: 37602

Middle Eastern (MID) AF: 0.00144 AC: 7 AN: 4876

European-Non Finnish (NFE) AF: 0.0110 AC: 12152 AN: 1106682

Other (OTH) AF: 0.00549 AC: 328 AN: 59692

GnomAD4 genome AF: 0.00533 AC: 811 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74412

African (AFR) AF: 0.00200 AC: 83 AN: 41526

American (AMR) AF: 0.00124 AC: 19 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00980 AC: 666 AN: 67964

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00544

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00232 AC: 10

ESP6500EA AF: 0.00852 AC: 72

ExAC AF: 0.00537 AC: 642

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.048	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.87
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.046
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.24	T
Polyphen		0.14	B
Vest4		0.40
MVP		0.84
MPC		0.0066
ClinPred		0.011	T
GERP RS		4.7
Varity_R		0.058
gMVP		0.51
Mutation Taster		=99/1	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; COSMIC: COSV104413811; COSMIC: COSV104413811;