2-217809974-C-T

Variant names:

• chr2-217809974-C-T
• rs918949
• NM_001387777.1:c.5122G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000682258.1(TNS1):​c.5122G>A​(p.Val1708Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,613,192 control chromosomes in the GnomAD database, including 293,610 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.64 (32124 hom., cov: 32)
  • Exomes 𝑓: 0.60 (261486 hom.)
• Consequence: TNS1 ENST00000682258.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.475
• Publications: 53 publications found

Genes affected

TNS1 (HGNC:11973): (tensin 1) The protein encoded by this gene localizes to focal adhesions, regions of the plasma membrane where the cell attaches to the extracellular matrix. This protein crosslinks actin filaments and contains a Src homology 2 (SH2) domain, which is often found in molecules involved in signal transduction. This protein is a substrate of calpain II. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4227002E-6).
• BP6: Variant 2-217809974-C-T is Benign according to our data. Variant chr2-217809974-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060255.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000682258.1. 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
	TNS1	NM_001387777.1	MANE Select	c.5122G>A	p.Val1708Ile	missense	Exon 30 of 33	NP_001374706.1
	TNS1	NM_001438865.1		c.5185G>A	p.Val1729Ile	missense	Exon 30 of 33	NP_001425794.1
	TNS1	NM_001438866.1		c.5119G>A	p.Val1707Ile	missense	Exon 30 of 33	NP_001425795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNS1	ENST00000682258.1	MANE Select	c.5122G>A	p.Val1708Ile	missense	Exon 30 of 33	ENSP00000506917.1
	TNS1	ENST00000171887.8	TSL:1	c.4810G>A	p.Val1604Ile	missense	Exon 30 of 33	ENSP00000171887.4
	TNS1	ENST00000419504.6	TSL:1	c.4768G>A	p.Val1590Ile	missense	Exon 29 of 32	ENSP00000408724.1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97663 AN: 151844 Hom.: 32073 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.624

GnomAD2 exomes AF: 0.595 AC: 149216 AN: 250916 AF XY: 0.586

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.673

Gnomad EAS exome AF: 0.511

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.596 AC: 870372 AN: 1461230 Hom.: 261486 Cov.: 56 AF XY: 0.592 AC XY: 430324 AN XY: 726852

African (AFR) AF: 0.782 AC: 26169 AN: 33472

American (AMR) AF: 0.630 AC: 28133 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 17452 AN: 26124

East Asian (EAS) AF: 0.458 AC: 18164 AN: 39688

South Asian (SAS) AF: 0.480 AC: 41410 AN: 86202

European-Finnish (FIN) AF: 0.549 AC: 29263 AN: 53346

Middle Eastern (MID) AF: 0.674 AC: 3883 AN: 5760

European-Non Finnish (NFE) AF: 0.602 AC: 669560 AN: 1111588

Other (OTH) AF: 0.602 AC: 36338 AN: 60368

GnomAD4 genome AF: 0.643 AC: 97773 AN: 151962 Hom.: 32124 Cov.: 32 AF XY: 0.638 AC XY: 47414 AN XY: 74278

African (AFR) AF: 0.778 AC: 32270 AN: 41498

American (AMR) AF: 0.635 AC: 9704 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2325 AN: 3470

East Asian (EAS) AF: 0.505 AC: 2600 AN: 5144

South Asian (SAS) AF: 0.489 AC: 2344 AN: 4798

European-Finnish (FIN) AF: 0.536 AC: 5644 AN: 10530

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.602 AC: 40894 AN: 67930

Other (OTH) AF: 0.624 AC: 1315 AN: 2106

Alfa AF: 0.623 Hom.: 92686

Bravo AF: 0.659

TwinsUK AF: 0.606 AC: 2246

ALSPAC AF: 0.615 AC: 2369

ESP6500AA AF: 0.768 AC: 3386

ESP6500EA AF: 0.611 AC: 5251

ExAC AF: 0.595 AC: 72180

Asia WGS AF: 0.515 AC: 1792 AN: 3478

EpiCase AF: 0.616

EpiControl AF: 0.611

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TNS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.59
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0000024	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.47
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.061
Sift	Benign	0.87	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.099
ClinPred		0.0084	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.10
Mutation Taster		=100/0	polymorphism (auto)

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: rs918949; hg19: chr2-218674697; COSMIC: COSV50691115; COSMIC: COSV50691115;