dbSNP rs7241380: PIEZO2:p.Leu1027Leu (chr18-10762964-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The NM_001378183.1(PIEZO2):c.3081C>T(p.Leu1027Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,536,988 control chromosomes in the GnomAD database, including 481,780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 46624 hom., cov: 35)

Exomes 𝑓: 0.79 ( 435156 hom. )

Consequence

PIEZO2
NM_001378183.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.286

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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
arthrogryposis, distal, with impaired proprioception and touch
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
connective tissue disorder
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
Marden-Walker syndrome
Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics

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=-0.77).

BP6

Variant 18-10762964-G-A is Benign according to our data. Variant chr18-10762964-G-A is described in ClinVar as Benign. ClinVar VariationId is 261505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.286 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378183.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO2	NM_001378183.1	MANE Select	c.3081C>T	p.Leu1027Leu	synonymous	Exon 22 of 56	NP_001365112.1	A0A2H4UKA7
PIEZO2	NM_001410871.1		c.3081C>T	p.Leu1027Leu	synonymous	Exon 22 of 54	NP_001397800.1	Q9H5I5-4
PIEZO2	NM_022068.4		c.3006C>T	p.Leu1002Leu	synonymous	Exon 20 of 52	NP_071351.2	Q9H5I5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO2	ENST00000674853.1	MANE Select	c.3081C>T	p.Leu1027Leu	synonymous	Exon 22 of 56	ENSP00000501957.1	A0A2H4UKA7
PIEZO2	ENST00000503781.7	TSL:1	c.3006C>T	p.Leu1002Leu	synonymous	Exon 20 of 52	ENSP00000421377.3	Q9H5I5-1
PIEZO2	ENST00000580640.5	TSL:5	c.3081C>T	p.Leu1027Leu	synonymous	Exon 22 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes

AF:

0.782

AC:

118939

AN:

152098

Hom.:

46596

Cov.:

show subpopulations

Gnomad AFR

AF:

0.777

Gnomad AMI

AF:

0.710

Gnomad AMR

AF:

0.728

Gnomad ASJ

AF:

0.846

Gnomad EAS

AF:

0.881

Gnomad SAS

AF:

0.759

Gnomad FIN

AF:

0.788

Gnomad MID

AF:

0.829

Gnomad NFE

AF:

0.788

Gnomad OTH

AF:

0.782

GnomAD2 exomes

AF:

0.775

AC:

111788

AN:

144308

AF XY:

0.777

show subpopulations

Gnomad AFR exome

AF:

0.783

Gnomad AMR exome

AF:

0.671

Gnomad ASJ exome

AF:

0.840

Gnomad EAS exome

AF:

0.881

Gnomad FIN exome

AF:

0.775

Gnomad NFE exome

AF:

0.794

Gnomad OTH exome

AF:

0.788

GnomAD4 exome

AF:

0.792

AC:

1096951

AN:

1384772

Hom.:

435156

Cov.:

AF XY:

0.791

AC XY:

540664

AN XY:

683318

show subpopulations

African (AFR)

AF:

0.776

AC:

24500

AN:

31586

American (AMR)

AF:

0.680

AC:

24269

AN:

35694

Ashkenazi Jewish (ASJ)

AF:

0.838

AC:

21097

AN:

25182

East Asian (EAS)

AF:

0.880

AC:

31434

AN:

35730

South Asian (SAS)

AF:

0.761

AC:

60310

AN:

79214

European-Finnish (FIN)

AF:

0.775

AC:

27138

AN:

35000

Middle Eastern (MID)

AF:

0.823

AC:

4685

AN:

5694

European-Non Finnish (NFE)

AF:

0.795

AC:

857255

AN:

1078762

Other (OTH)

AF:

0.799

AC:

46263

AN:

57910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

12888

25776

38663

51551

64439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20404

40808

61212

81616

102020

<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:

0.782

AC:

119013

AN:

152216

Hom.:

46624

Cov.:

AF XY:

0.782

AC XY:

58207

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.776

AC:

32231

AN:

41530

American (AMR)

AF:

0.728

AC:

11140

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.846

AC:

2939

AN:

3472

East Asian (EAS)

AF:

0.881

AC:

4557

AN:

5172

South Asian (SAS)

AF:

0.760

AC:

3671

AN:

4828

European-Finnish (FIN)

AF:

0.788

AC:

8340

AN:

10580

Middle Eastern (MID)

AF:

0.833

AC:

245

AN:

294

European-Non Finnish (NFE)

AF:

0.788

AC:

53585

AN:

68016

Other (OTH)

AF:

0.785

AC:

1659

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1356

2713

4069

5426

6782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.781

Hom.:

16779

Bravo

AF:

0.780

Asia WGS

AF:

0.846

AC:

2942

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome (1)

Arthrogryposis, distal, with impaired proprioception and touch (1)

Gordon syndrome (1)

Marden-Walker syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.6

(source)

DANN

Benign

0.71

PhyloP100

-0.29

Mutation Taster

=99/1

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

Computational scores

Splicing

Publications

Other links and lift over