Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000674853.1(PIEZO2):c.2226T>C(p.Ile742Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,535,012 control chromosomes in the GnomAD database, including 3,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 286 hom., cov: 33)

Exomes 𝑓: 0.065 ( 3193 hom. )

Consequence

PIEZO2
ENST00000674853.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.00600

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 18-10787128-A-G is Benign according to our data. Variant chr18-10787128-A-G is described in ClinVar as Benign. ClinVar VariationId is 261502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.006 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000674853.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIEZO2	NM_001378183.1	MANE Select	c.2226T>C	p.Ile742Ile	synonymous	Exon 16 of 56	NP_001365112.1
PIEZO2	NM_001410871.1		c.2226T>C	p.Ile742Ile	synonymous	Exon 16 of 54	NP_001397800.1
PIEZO2	NM_022068.4		c.2226T>C	p.Ile742Ile	synonymous	Exon 16 of 52	NP_071351.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIEZO2	ENST00000674853.1	MANE Select	c.2226T>C	p.Ile742Ile	synonymous	Exon 16 of 56	ENSP00000501957.1
PIEZO2	ENST00000503781.7	TSL:1	c.2226T>C	p.Ile742Ile	synonymous	Exon 16 of 52	ENSP00000421377.3
PIEZO2	ENST00000580640.5	TSL:5	c.2226T>C	p.Ile742Ile	synonymous	Exon 16 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes

AF:

0.0552

AC:

8391

AN:

152136

Hom.:

286

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0435

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0429

Gnomad ASJ

AF:

0.0527

Gnomad EAS

AF:

0.00461

Gnomad SAS

AF:

0.0395

Gnomad FIN

AF:

0.0869

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0658

Gnomad OTH

AF:

0.0595

GnomAD2 exomes

AF:

0.0499

AC:

7159

AN:

143490

AF XY:

0.0502

show subpopulations

Gnomad AFR exome

AF:

0.0437

Gnomad AMR exome

AF:

0.0370

Gnomad ASJ exome

AF:

0.0475

Gnomad EAS exome

AF:

0.00217

Gnomad FIN exome

AF:

0.0853

Gnomad NFE exome

AF:

0.0633

Gnomad OTH exome

AF:

0.0554

GnomAD4 exome

AF:

0.0653

AC:

90341

AN:

1382758

Hom.:

3193

Cov.:

AF XY:

0.0646

AC XY:

44082

AN XY:

682276

show subpopulations

African (AFR)

AF:

0.0432

AC:

1363

AN:

31516

American (AMR)

AF:

0.0412

AC:

1464

AN:

35520

Ashkenazi Jewish (ASJ)

AF:

0.0506

AC:

1272

AN:

25144

East Asian (EAS)

AF:

0.00109

AC:

AN:

35680

South Asian (SAS)

AF:

0.0427

AC:

3366

AN:

78828

European-Finnish (FIN)

AF:

0.0842

AC:

2947

AN:

34982

Middle Eastern (MID)

AF:

0.0293

AC:

165

AN:

5632

European-Non Finnish (NFE)

AF:

0.0708

AC:

76307

AN:

1077618

Other (OTH)

AF:

0.0591

AC:

3418

AN:

57838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

4107

8214

12320

16427

20534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2934

5868

8802

11736

14670

<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:

0.0551

AC:

8395

AN:

152254

Hom.:

286

Cov.:

AF XY:

0.0554

AC XY:

4121

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0435

AC:

1806

AN:

41556

American (AMR)

AF:

0.0428

AC:

655

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0527

AC:

183

AN:

3472

East Asian (EAS)

AF:

0.00462

AC:

AN:

5194

South Asian (SAS)

AF:

0.0391

AC:

189

AN:

4830

European-Finnish (FIN)

AF:

0.0869

AC:

919

AN:

10576

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0659

AC:

4479

AN:

68012

Other (OTH)

AF:

0.0594

AC:

125

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

384

767

1151

1534

1918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0551

Hom.:

Bravo

AF:

0.0523

Asia WGS

AF:

0.0240

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

7.0

(source)

DANN

Benign

0.77

PhyloP100

-0.0060

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over