18-10691218-G-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.7349+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,610,936 control chromosomes in the GnomAD database, including 110,021 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 9846 hom., cov: 31)

Exomes 𝑓: 0.37 ( 100175 hom. )

Consequence

PIEZO2
NM_001378183.1 splice_region, intron

Scores

Splicing: ADA: 0.00008783

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.471

Publications

12 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 (BayesDel_noAF=-0.83).

BP6

Variant 18-10691218-G-A is Benign according to our data. Variant chr18-10691218-G-A is described in CliVar as Benign. Clinvar id is 261527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10691218-G-A is described in CliVar as Benign. Clinvar id is 261527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10691218-G-A is described in CliVar as Benign. Clinvar id is 261527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10691218-G-A is described in CliVar as Benign. Clinvar id is 261527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10691218-G-A is described in CliVar as Benign. Clinvar id is 261527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10691218-G-A is described in CliVar as Benign. Clinvar id is 261527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10691218-G-A is described in CliVar as Benign. Clinvar id is 261527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.7349+7C>T		splice_region_variant, intron_variant	Intron 48 of 55	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1 link	c.7349+7C>T		splice_region_variant, intron_variant	Intron 48 of 55		NM_001378183.1	ENSP00000501957.1		A0A2H4UKA7

Frequencies

GnomAD3 genomes

AF:

0.360

AC:

54617

AN:

151788

Hom.:

9841

Cov.:

show subpopulations

Gnomad AFR

AF:

0.354

Gnomad AMI

AF:

0.336

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.307

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.290

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.366

GnomAD2 exomes

AF:

0.345

AC:

86175

AN:

249850

AF XY:

0.344

show subpopulations

Gnomad AFR exome

AF:

0.352

Gnomad AMR exome

AF:

0.285

Gnomad ASJ exome

AF:

0.386

Gnomad EAS exome

AF:

0.297

Gnomad FIN exome

AF:

0.362

Gnomad NFE exome

AF:

0.380

Gnomad OTH exome

AF:

0.346

GnomAD4 exome

AF:

0.368

AC:

537299

AN:

1459030

Hom.:

100175

Cov.:

AF XY:

0.366

AC XY:

265510

AN XY:

725874

show subpopulations

African (AFR)

AF:

0.350

AC:

11693

AN:

33426

American (AMR)

AF:

0.291

AC:

12930

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.383

AC:

9984

AN:

26086

East Asian (EAS)

AF:

0.374

AC:

14807

AN:

39636

South Asian (SAS)

AF:

0.281

AC:

24116

AN:

85896

European-Finnish (FIN)

AF:

0.359

AC:

19194

AN:

53398

Middle Eastern (MID)

AF:

0.318

AC:

1832

AN:

5752

European-Non Finnish (NFE)

AF:

0.380

AC:

421386

AN:

1110040

Other (OTH)

AF:

0.354

AC:

21357

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

15953

31906

47859

63812

79765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13152

26304

39456

52608

65760

<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:

0.360

AC:

54637

AN:

151906

Hom.:

9846

Cov.:

AF XY:

0.357

AC XY:

26465

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.353

AC:

14632

AN:

41406

American (AMR)

AF:

0.317

AC:

4846

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

1376

AN:

3472

East Asian (EAS)

AF:

0.308

AC:

1587

AN:

5154

South Asian (SAS)

AF:

0.260

AC:

1250

AN:

4804

European-Finnish (FIN)

AF:

0.363

AC:

3820

AN:

10536

Middle Eastern (MID)

AF:

0.281

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.382

AC:

25975

AN:

67956

Other (OTH)

AF:

0.362

AC:

763

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1825

3650

5475

7300

9125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.369

Hom.:

7195

Bravo

AF:

0.354

Asia WGS

AF:

0.264

AC:

921

AN:

3478

EpiCase

AF:

0.380

EpiControl

AF:

0.368

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

- -

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

-0.83

CADD

Benign

3.7

(source)

DANN

Benign

0.38

PhyloP100

-0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000088

dbscSNV1_RF

Benign

0.0

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