18-10731430-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378183.1(PIEZO2):c.5006G>A(p.Arg1669Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,532,860 control chromosomes in the GnomAD database, including 50,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3597 hom., cov: 30)

Exomes 𝑓: 0.26 ( 47399 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.149

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

Gordon syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
arthrogryposis, distal, with impaired proprioception and touch
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
connective tissue disorder
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
Marden-Walker syndrome
Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet

PIEZO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004354328).

BP6

Variant 18-10731430-C-T is Benign according to our data. Variant chr18-10731430-C-T is described in ClinVar as Benign. ClinVar VariationId is 261511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.5006G>A	p.Arg1669Gln	missense_variant	Exon 36 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.5006G>A	p.Arg1669Gln	missense_variant	Exon 36 of 56		NM_001378183.1	ENSP00000501957.1		A0A2H4UKA7

Frequencies

GnomAD3 genomes

AF:

0.204

AC:

30966

AN:

151460

Hom.:

3595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0865

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.211

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.229

Gnomad NFE

AF:

0.273

Gnomad OTH

AF:

0.204

GnomAD2 exomes

AF:

0.220

AC:

30682

AN:

139548

AF XY:

0.226

show subpopulations

Gnomad AFR exome

AF:

0.0785

Gnomad AMR exome

AF:

0.154

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.231

GnomAD4 exome

AF:

0.257

AC:

355080

AN:

1381282

Hom.:

47399

Cov.:

AF XY:

0.257

AC XY:

175221

AN XY:

681710

show subpopulations

African (AFR)

AF:

0.0773

AC:

2427

AN:

31400

American (AMR)

AF:

0.159

AC:

5603

AN:

35288

Ashkenazi Jewish (ASJ)

AF:

0.242

AC:

6065

AN:

25108

East Asian (EAS)

AF:

0.135

AC:

4788

AN:

35516

South Asian (SAS)

AF:

0.225

AC:

17751

AN:

78922

European-Finnish (FIN)

AF:

0.254

AC:

8874

AN:

34920

Middle Eastern (MID)

AF:

0.259

AC:

1475

AN:

5686

European-Non Finnish (NFE)

AF:

0.273

AC:

294186

AN:

1076720

Other (OTH)

AF:

0.241

AC:

13911

AN:

57722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

11557

23114

34670

46227

57784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9772

19544

29316

39088

48860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.204

AC:

30959

AN:

151578

Hom.:

3597

Cov.:

AF XY:

0.203

AC XY:

15047

AN XY:

74062

show subpopulations

African (AFR)

AF:

0.0862

AC:

3568

AN:

41404

American (AMR)

AF:

0.193

AC:

2931

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

884

AN:

3466

East Asian (EAS)

AF:

0.125

AC:

640

AN:

5136

South Asian (SAS)

AF:

0.210

AC:

1012

AN:

4808

European-Finnish (FIN)

AF:

0.262

AC:

2725

AN:

10404

Middle Eastern (MID)

AF:

0.240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.273

AC:

18500

AN:

67842

Other (OTH)

AF:

0.202

AC:

424

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1125

2249

3374

4498

5623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.241

Hom.:

10303

Bravo

AF:

0.193

TwinsUK

AF:

0.258

AC:

957

ALSPAC

AF:

0.274

AC:

1057

ESP6500AA

AF:

0.103

AC:

143

ESP6500EA

AF:

0.279

AC:

889

ExAC

AF:

0.203

AC:

4574

Asia WGS

AF:

0.155

AC:

540

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

Oct 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.060

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0034

.;T;.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.;L

PhyloP100

-0.15

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.39

N;.;.;.

REVEL

Benign

0.042

Sift

Benign

0.35

T;.;.;.

Sift4G

Benign

0.55

T;T;T;T

Vest4

0.099

MPC

0.35

ClinPred

0.00049

GERP RS

2.6

Varity_R

0.014

gMVP

0.23

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over