NM_001378183.1:c.4135G>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.4135G>A(p.Val1379Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,536,748 control chromosomes in the GnomAD database, including 60,652 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7345 hom., cov: 33)

Exomes 𝑓: 0.27 ( 53307 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.84

Publications

21 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=8.2963705E-4).

BP6

Variant 18-10752668-C-T is Benign according to our data. Variant chr18-10752668-C-T is described in ClinVar as Benign. ClinVar VariationId is 261508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.4135G>A	p.Val1379Ile	missense_variant	Exon 28 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.4135G>A	p.Val1379Ile	missense_variant	Exon 28 of 56		NM_001378183.1	ENSP00000501957.1		A0A2H4UKA7

Frequencies

GnomAD3 genomes

AF:

0.303

AC:

46037

AN:

151934

Hom.:

7327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.390

Gnomad AMI

AF:

0.353

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.473

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.208

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.270

Gnomad OTH

AF:

0.303

GnomAD2 exomes

AF:

0.272

AC:

38581

AN:

141626

AF XY:

0.271

show subpopulations

Gnomad AFR exome

AF:

0.398

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.277

Gnomad EAS exome

AF:

0.491

Gnomad FIN exome

AF:

0.218

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.286

GnomAD4 exome

AF:

0.274

AC:

378916

AN:

1384696

Hom.:

53307

Cov.:

AF XY:

0.271

AC XY:

185349

AN XY:

683280

show subpopulations

African (AFR)

AF:

0.395

AC:

12470

AN:

31584

American (AMR)

AF:

0.192

AC:

6843

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

6922

AN:

25182

East Asian (EAS)

AF:

0.437

AC:

15622

AN:

35734

South Asian (SAS)

AF:

0.228

AC:

18042

AN:

79226

European-Finnish (FIN)

AF:

0.225

AC:

7856

AN:

34984

Middle Eastern (MID)

AF:

0.318

AC:

1810

AN:

5696

European-Non Finnish (NFE)

AF:

0.271

AC:

292507

AN:

1078694

Other (OTH)

AF:

0.291

AC:

16844

AN:

57900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

14706

29412

44117

58823

73529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10074

20148

30222

40296

50370

<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:

0.303

AC:

46077

AN:

152052

Hom.:

7345

Cov.:

AF XY:

0.301

AC XY:

22391

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.390

AC:

16149

AN:

41454

American (AMR)

AF:

0.241

AC:

3680

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

936

AN:

3472

East Asian (EAS)

AF:

0.473

AC:

2443

AN:

5168

South Asian (SAS)

AF:

0.246

AC:

1187

AN:

4818

European-Finnish (FIN)

AF:

0.208

AC:

2203

AN:

10566

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.270

AC:

18384

AN:

67970

Other (OTH)

AF:

0.311

AC:

657

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1632

3264

4896

6528

8160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.289

Hom.:

12984

Bravo

AF:

0.315

TwinsUK

AF:

0.281

AC:

1043

ALSPAC

AF:

0.265

AC:

1021

ESP6500AA

AF:

0.397

AC:

549

ESP6500EA

AF:

0.271

AC:

863

ExAC

AF:

0.245

AC:

4919

Asia WGS

AF:

0.385

AC:

1338

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 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

- -

Jul 05, 2018

GeneDx

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

- -

Gordon syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Marden-Walker syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arthrogryposis, distal, with impaired proprioception and touch

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

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

0.077

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.025

.;T;.;T

Eigen

Benign

0.097

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.87

D;D;D;D

MetaRNN

Benign

0.00083

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

L;.;.;L

PhyloP100

1.8

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.53

N;.;.;.

REVEL

Benign

0.056

Sift

Benign

0.24

T;.;.;.

Sift4G

Benign

0.14

T;T;T;T

Vest4

0.17

MPC

0.25

ClinPred

0.0068

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.045

gMVP

0.54

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

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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