rs147666072

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378183.1(PIEZO2):c.7969G>A(p.Ala2657Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,590,704 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 6 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 6.37

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038327932).

BP6

Variant 18-10677859-C-T is Benign according to our data. Variant chr18-10677859-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445793.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00112 (165/147884) while in subpopulation NFE AF= 0.00169 (113/67058). AF 95% confidence interval is 0.00143. There are 1 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.7969G>A	p.Ala2657Thr	missense_variant	Exon 53 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.7969G>A	p.Ala2657Thr	missense_variant	Exon 53 of 56		NM_001378183.1	ENSP00000501957.1		A0A2H4UKA7

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

165

AN:

147766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000902

Gnomad ASJ

AF:

0.00585

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000224

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00327

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.000503

GnomAD3 exomes

AF:

0.00106

AC:

239

AN:

226266

Hom.:

AF XY:

0.00114

AC XY:

140

AN XY:

122642

show subpopulations

Gnomad AFR exome

AF:

0.000512

Gnomad AMR exome

AF:

0.000540

Gnomad ASJ exome

AF:

0.00609

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000122

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.00129

AC:

1868

AN:

1442820

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

924

AN XY:

717126

show subpopulations

Gnomad4 AFR exome

AF:

0.000218

Gnomad4 AMR exome

AF:

0.000655

Gnomad4 ASJ exome

AF:

0.00479

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000270

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.00146

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00112

AC:

165

AN:

147884

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

AN XY:

71898

show subpopulations

Gnomad4 AFR

AF:

0.000397

Gnomad4 AMR

AF:

0.000901

Gnomad4 ASJ

AF:

0.00585

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000224

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00169

Gnomad4 OTH

AF:

0.000498

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000840

AC:

102

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00219

EpiControl

AF:

0.00192

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

May 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7630G>A (p.A2544T) alteration is located in exon 49 (coding exon 49) of the PIEZO2 gene. This alteration results from a G to A substitution at nucleotide position 7630, causing the alanine (A) at amino acid position 2544 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Arthrogryposis, distal, with impaired proprioception and touch

Uncertain:1

Mar 01, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6. -

PIEZO2-related disorder

Benign:1

Apr 29, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

.;D;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.038

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.8

.;.;.;M

PrimateAI

Uncertain

0.51

REVEL

Uncertain

0.40

Sift4G

Uncertain

0.031

D;D;D;D

Vest4

0.74

MVP

0.043

MPC

0.89

ClinPred

0.035

GERP RS

5.6

Varity_R

0.27

gMVP

0.38

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

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