NM_001378183.1:c.6488C>A

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.6488C>A(p.Ala2163Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0798 in 1,537,064 control chromosomes in the GnomAD database, including 6,147 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2163T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 1370 hom., cov: 32)

Exomes 𝑓: 0.077 ( 4777 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.37

Publications

5 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=0.0018732846).

BP6

Variant 18-10699131-G-T is Benign according to our data. Variant chr18-10699131-G-T is described in ClinVar as Benign. ClinVar VariationId is 261521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.6488C>A	p.Ala2163Asp	missense_variant	Exon 44 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.6488C>A	p.Ala2163Asp	missense_variant	Exon 44 of 56		NM_001378183.1	ENSP00000501957.1		A0A2H4UKA7

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16655

AN:

152036

Hom.:

1356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0667

Gnomad ASJ

AF:

0.0674

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.0613

Gnomad FIN

AF:

0.0611

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0694

Gnomad OTH

AF:

0.0915

GnomAD2 exomes

AF:

0.0697

AC:

9874

AN:

141580

AF XY:

0.0683

show subpopulations

Gnomad AFR exome

AF:

0.240

Gnomad AMR exome

AF:

0.0508

Gnomad ASJ exome

AF:

0.0645

Gnomad EAS exome

AF:

0.00141

Gnomad FIN exome

AF:

0.0554

Gnomad NFE exome

AF:

0.0708

Gnomad OTH exome

AF:

0.0612

GnomAD4 exome

AF:

0.0766

AC:

106025

AN:

1384910

Hom.:

4777

Cov.:

AF XY:

0.0757

AC XY:

51723

AN XY:

683384

show subpopulations

African (AFR)

AF:

0.239

AC:

7565

AN:

31594

American (AMR)

AF:

0.0562

AC:

2005

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.0641

AC:

1615

AN:

25182

East Asian (EAS)

AF:

0.000784

AC:

AN:

35734

South Asian (SAS)

AF:

0.0681

AC:

5395

AN:

79234

European-Finnish (FIN)

AF:

0.0561

AC:

1965

AN:

34998

Middle Eastern (MID)

AF:

0.0400

AC:

228

AN:

5694

European-Non Finnish (NFE)

AF:

0.0768

AC:

82824

AN:

1078860

Other (OTH)

AF:

0.0760

AC:

4400

AN:

57914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

5533

11066

16600

22133

27666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3306

6612

9918

13224

16530

<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:

0.110

AC:

16686

AN:

152154

Hom.:

1370

Cov.:

AF XY:

0.107

AC XY:

7935

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.230

AC:

9555

AN:

41472

American (AMR)

AF:

0.0664

AC:

1015

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0674

AC:

234

AN:

3470

East Asian (EAS)

AF:

0.00290

AC:

AN:

5180

South Asian (SAS)

AF:

0.0612

AC:

295

AN:

4822

European-Finnish (FIN)

AF:

0.0611

AC:

647

AN:

10594

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0694

AC:

4719

AN:

68010

Other (OTH)

AF:

0.0896

AC:

189

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

723

1447

2170

2894

3617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0799

Hom.:

1209

Bravo

AF:

0.117

TwinsUK

AF:

0.0825

AC:

306

ALSPAC

AF:

0.0812

AC:

313

ExAC

AF:

0.0751

AC:

1612

Asia WGS

AF:

0.0490

AC:

171

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arthrogryposis, distal, with impaired proprioception and touch

Benign:1

May 28, 2019

Mendelics

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

0.057

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.7

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.0043

.;T;.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.27

T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.6

N;.;.;N

PhyloP100

1.4

PrimateAI

Benign

0.35

PROVEAN

Benign

1.9

N;.;.;.

REVEL

Benign

0.13

Sift

Benign

0.78

T;.;.;.

Sift4G

Benign

0.68

T;T;T;T

Vest4

0.085

MPC

0.45

ClinPred

0.0029

GERP RS

5.8

Varity_R

0.036

gMVP

0.41

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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