rs35033671

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378183.1(PIEZO2):c.3518G>T(p.Cys1173Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,537,210 control chromosomes in the GnomAD database, including 31,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2561 hom., cov: 32)

Exomes 𝑓: 0.20 ( 28947 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.55

Variant links:

Genes affected

PIEZO2 (HGNC:26270): (piezo type mechanosensitive ion channel component 2) The protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels. These channels serve to connect mechanical forces to biological signals. The encoded protein quickly adapts MA currents in somatosensory neurons. Defects in this gene are a cause of type 5 distal arthrogryposis. Several alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2014]

PIEZO2 links:

MIR6788 (HGNC:50078): (microRNA 6788) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6788 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017485023).

BP6

Variant 18-10759842-C-A is Benign according to our data. Variant chr18-10759842-C-A is described in ClinVar as [Benign]. Clinvar id is 261506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10759842-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.3518G>T	p.Cys1173Phe	missense_variant	Exon 25 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1 link	c.3518G>T	p.Cys1173Phe	missense_variant	Exon 25 of 56		NM_001378183.1	ENSP00000501957.1		A0A2H4UKA7

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24737

AN:

152072

Hom.:

2562

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0391

Gnomad AMI

AF:

0.289

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.0882

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.212

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.175

GnomAD3 exomes

AF:

0.204

AC:

29685

AN:

145282

Hom.:

3383

AF XY:

0.207

AC XY:

16008

AN XY:

77356

show subpopulations

Gnomad AFR exome

AF:

0.0363

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.160

Gnomad EAS exome

AF:

0.0897

Gnomad SAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.225

Gnomad NFE exome

AF:

0.205

Gnomad OTH exome

AF:

0.193

GnomAD4 exome

AF:

0.201

AC:

277759

AN:

1385020

Hom.:

28947

Cov.:

AF XY:

0.202

AC XY:

138379

AN XY:

683406

show subpopulations

Gnomad4 AFR exome

AF:

0.0325

Gnomad4 AMR exome

AF:

0.270

Gnomad4 ASJ exome

AF:

0.162

Gnomad4 EAS exome

AF:

0.0993

Gnomad4 SAS exome

AF:

0.243

Gnomad4 FIN exome

AF:

0.226

Gnomad4 NFE exome

AF:

0.204

Gnomad4 OTH exome

AF:

0.186

GnomAD4 genome

AF:

0.163

AC:

24733

AN:

152190

Hom.:

2561

Cov.:

AF XY:

0.164

AC XY:

12203

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0391

Gnomad4 AMR

AF:

0.239

Gnomad4 ASJ

AF:

0.153

Gnomad4 EAS

AF:

0.0882

Gnomad4 SAS

AF:

0.242

Gnomad4 FIN

AF:

0.212

Gnomad4 NFE

AF:

0.212

Gnomad4 OTH

AF:

0.172

Alfa

AF:

0.196

Hom.:

3815

Bravo

AF:

0.157

TwinsUK

AF:

0.214

AC:

792

ALSPAC

AF:

0.215

AC:

827

ESP6500AA

AF:

0.0368

AC:

ESP6500EA

AF:

0.209

AC:

664

ExAC

AF:

0.183

AC:

4344

Asia WGS

AF:

0.128

AC:

444

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.10

.;T;.;T

Eigen

Benign

-0.072

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

T;T;D;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.12

N;.;.;N

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-6.7

D;.;.;.

REVEL

Benign

0.16

Sift

Benign

0.17

T;.;.;.

Sift4G

Benign

0.29

T;T;T;T

Polyphen

0.0

.;.;B;.

Vest4

0.22

MPC

0.46

ClinPred

0.031

GERP RS

5.0

Varity_R

0.49

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over