rs3748421

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001378183.1(PIEZO2):c.7215C>T(p.Ala2405Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,610,936 control chromosomes in the GnomAD database, including 88,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6284 hom., cov: 31)

Exomes 𝑓: 0.33 ( 82265 hom. )

Consequence

PIEZO2
NM_001378183.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.584

Publications

17 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 18-10691359-G-A is Benign according to our data. Variant chr18-10691359-G-A is described in ClinVar as Benign. ClinVar VariationId is 261526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.584 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.7215C>T	p.Ala2405Ala	synonymous_variant	Exon 48 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.7215C>T	p.Ala2405Ala	synonymous_variant	Exon 48 of 56		NM_001378183.1	ENSP00000501957.1		A0A2H4UKA7

Frequencies

GnomAD3 genomes

AF:

0.274

AC:

41579

AN:

151860

Hom.:

6282

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.355

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.323

Gnomad MID

AF:

0.271

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.288

GnomAD2 exomes

AF:

0.282

AC:

70105

AN:

248420

AF XY:

0.289

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.347

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.324

Gnomad NFE exome

AF:

0.353

Gnomad OTH exome

AF:

0.298

GnomAD4 exome

AF:

0.330

AC:

480888

AN:

1458956

Hom.:

82265

Cov.:

AF XY:

0.329

AC XY:

238437

AN XY:

725722

show subpopulations

African (AFR)

AF:

0.151

AC:

5021

AN:

33360

American (AMR)

AF:

0.184

AC:

8186

AN:

44382

Ashkenazi Jewish (ASJ)

AF:

0.346

AC:

9021

AN:

26078

East Asian (EAS)

AF:

0.137

AC:

5427

AN:

39508

South Asian (SAS)

AF:

0.260

AC:

22282

AN:

85700

European-Finnish (FIN)

AF:

0.322

AC:

17171

AN:

53368

Middle Eastern (MID)

AF:

0.278

AC:

1600

AN:

5758

European-Non Finnish (NFE)

AF:

0.354

AC:

393552

AN:

1110524

Other (OTH)

AF:

0.309

AC:

18628

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

15332

30663

45995

61326

76658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12268

24536

36804

49072

61340

<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:

0.274

AC:

41589

AN:

151980

Hom.:

6284

Cov.:

AF XY:

0.270

AC XY:

20066

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.159

AC:

6587

AN:

41456

American (AMR)

AF:

0.238

AC:

3628

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.355

AC:

1233

AN:

3470

East Asian (EAS)

AF:

0.108

AC:

560

AN:

5166

South Asian (SAS)

AF:

0.238

AC:

1150

AN:

4822

European-Finnish (FIN)

AF:

0.323

AC:

3405

AN:

10532

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.354

AC:

24049

AN:

67964

Other (OTH)

AF:

0.285

AC:

601

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1527

3054

4581

6108

7635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.313

Hom.:

6185

Bravo

AF:

0.259

Asia WGS

AF:

0.170

AC:

595

AN:

3478

EpiCase

AF:

0.353

EpiControl

AF:

0.343

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 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

- -

Oct 30, 2019

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

BayesDel_noAF

Benign

-0.43

CADD

Benign

4.0

(source)

DANN

Benign

0.80

PhyloP100

0.58

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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