12-53051905-A-T

Variant names:

• chr12-53051905-A-T
• rs751421693
• NM_170754.4:c.126A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_170754.4(TNS2):​c.126A>T​(p.Lys42Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNS2 NM_170754.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.158

Genes affected

TNS2 (HGNC:19737): (tensin 2) The protein encoded by this gene belongs to the tensin family. Tensin is a focal adhesion molecule that binds to actin filaments and participates in signaling pathways. This protein plays a role in regulating cell migration. Alternative splicing occurs at this locus and three transcript variants encoding three distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

TNS2-AS1 (HGNC:27464): (TNS2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 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
TNS2	NM_170754.4	c.126A>T	p.Lys42Asn	missense_variant	Exon 2 of 29	ENST00000314250.11	NP_736610.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNS2	ENST00000314250.11	c.126A>T	p.Lys42Asn	missense_variant	Exon 2 of 29	1	NM_170754.4	ENSP00000319684.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250920 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461354 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 52 of the TNS2 protein (p.Lys52Asn). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TNS2-related conditions. This variant is present in population databases (rs751421693, gnomAD 0.003%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;.;.;T
Eigen	Benign	0.000024
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.50	D;D;D;D;D
MetaSVM	Uncertain	0.58	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.034	D;T;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.48
MutPred		0.51		.;Gain of catalytic residue at P43 (P = 0);Gain of catalytic residue at P43 (P = 0);Gain of catalytic residue at P43 (P = 0);Gain of catalytic residue at P43 (P = 0);
MVP		0.32
MPC		0.75
ClinPred		0.90	D
GERP RS		-0.11
Varity_R		0.21
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs751421693; hg19: chr12-53445689;