chr2-217818431-A-G

Variant names:

• chr2-217818431-A-G
• rs2571445
• NM_001387777.1:c.3901T>C

Variant summary

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

The NM_001387777.1(TNS1):​c.3901T>C​(p.Trp1301Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,613,836 control chromosomes in the GnomAD database, including 306,254 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (33990 hom., cov: 34)
  • Exomes 𝑓: 0.61 (272264 hom.)
• Consequence: TNS1 NM_001387777.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.70
• Publications: 112 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=1.3957009E-6).
• BP6: Variant 2-217818431-A-G is Benign according to our data. Variant chr2-217818431-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060903.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387777.1. 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
	TNS1	NM_001387777.1	MANE Select	c.3901T>C	p.Trp1301Arg	missense	Exon 24 of 33	NP_001374706.1	Q9HBL0-3
	TNS1	NM_001438865.1		c.3964T>C	p.Trp1322Arg	missense	Exon 24 of 33	NP_001425794.1
	TNS1	NM_001438866.1		c.3901T>C	p.Trp1301Arg	missense	Exon 24 of 33	NP_001425795.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNS1	ENST00000682258.1	MANE Select	c.3901T>C	p.Trp1301Arg	missense	Exon 24 of 33	ENSP00000506917.1	Q9HBL0-3
	TNS1	ENST00000171887.8	TSL:1	c.3589T>C	p.Trp1197Arg	missense	Exon 24 of 33	ENSP00000171887.4	Q9HBL0-1
	TNS1	ENST00000419504.6	TSL:1	c.3550T>C	p.Trp1184Arg	missense	Exon 23 of 32	ENSP00000408724.1	E9PF55

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100438 AN: 152060 Hom.: 33935 Cov.: 34

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.645

GnomAD2 exomes AF: 0.618 AC: 155050 AN: 251032 AF XY: 0.610

Gnomad AFR exome AF: 0.812

Gnomad AMR exome AF: 0.646

Gnomad ASJ exome AF: 0.653

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.610

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.609 AC: 889818 AN: 1461660 Hom.: 272264 Cov.: 91 AF XY: 0.607 AC XY: 441328 AN XY: 727094

African (AFR) AF: 0.816 AC: 27326 AN: 33474

American (AMR) AF: 0.640 AC: 28621 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 16909 AN: 26132

East Asian (EAS) AF: 0.578 AC: 22928 AN: 39698

South Asian (SAS) AF: 0.554 AC: 47786 AN: 86236

European-Finnish (FIN) AF: 0.549 AC: 29284 AN: 53362

Middle Eastern (MID) AF: 0.704 AC: 4054 AN: 5762

European-Non Finnish (NFE) AF: 0.608 AC: 675611 AN: 1111900

Other (OTH) AF: 0.618 AC: 37299 AN: 60382

GnomAD4 genome AF: 0.661 AC: 100553 AN: 152176 Hom.: 33990 Cov.: 34 AF XY: 0.657 AC XY: 48842 AN XY: 74378

African (AFR) AF: 0.808 AC: 33560 AN: 41512

American (AMR) AF: 0.644 AC: 9853 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2272 AN: 3472

East Asian (EAS) AF: 0.621 AC: 3210 AN: 5172

South Asian (SAS) AF: 0.561 AC: 2706 AN: 4820

European-Finnish (FIN) AF: 0.533 AC: 5644 AN: 10590

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41231 AN: 68004

Other (OTH) AF: 0.645 AC: 1362 AN: 2110

Alfa AF: 0.629 Hom.: 98412

Bravo AF: 0.677

TwinsUK AF: 0.611 AC: 2265

ALSPAC AF: 0.615 AC: 2372

ESP6500AA AF: 0.801 AC: 3530

ESP6500EA AF: 0.614 AC: 5284

ExAC AF: 0.619 AC: 75169

Asia WGS AF: 0.606 AC: 2108 AN: 3478

EpiCase AF: 0.623

EpiControl AF: 0.617

ClinVar

ClinVar submissions

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	0.048
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.62
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.082	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.2	N
PhyloP100		2.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	3.8	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.18		Gain of methylation at W1197 (P = 0.0296)
MPC		0.22
ClinPred		0.00063	T
GERP RS		3.7
Varity_R		0.072
gMVP		0.33
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: rs2571445; hg19: chr2-218683154; COSMIC: COSV99409925; COSMIC: COSV99409925;