18-10979657-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378183.1(PIEZO2):c.164A>C(p.His55Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0162 in 1,533,854 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 27 hom., cov: 32)

Exomes 𝑓: 0.017 ( 226 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.49

Publications

5 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=0.009269655).

BP6

Variant 18-10979657-T-G is Benign according to our data. Variant chr18-10979657-T-G is described in ClinVar as Benign. ClinVar VariationId is 261499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1937/152302) while in subpopulation NFE AF = 0.0202 (1377/68036). AF 95% confidence interval is 0.0194. There are 27 homozygotes in GnomAd4. There are 912 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.164A>C	p.His55Pro	missense_variant	Exon 3 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.164A>C	p.His55Pro	missense_variant	Exon 3 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1937

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0134

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00885

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0202

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.0112

AC:

1575

AN:

140684

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00330

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.00540

Gnomad EAS exome

AF:

0.0000947

Gnomad FIN exome

AF:

0.00993

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.00954

GnomAD4 exome

AF:

0.0166

AC:

22886

AN:

1381552

Hom.:

226

Cov.:

AF XY:

0.0160

AC XY:

10919

AN XY:

681744

show subpopulations

African (AFR)

AF:

0.00289

AC:

AN:

31520

American (AMR)

AF:

0.00992

AC:

352

AN:

35476

Ashkenazi Jewish (ASJ)

AF:

0.00571

AC:

143

AN:

25056

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35690

South Asian (SAS)

AF:

0.00109

AC:

AN:

78862

European-Finnish (FIN)

AF:

0.00794

AC:

277

AN:

34904

Middle Eastern (MID)

AF:

0.00229

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0197

AC:

21190

AN:

1076616

Other (OTH)

AF:

0.0127

AC:

733

AN:

57746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1061

2122

3184

4245

5306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.0127

AC:

1937

AN:

152302

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

912

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00366

AC:

152

AN:

41556

American (AMR)

AF:

0.0133

AC:

204

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00885

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0202

AC:

1377

AN:

68036

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

101

201

302

402

503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0172

Hom.:

Bravo

AF:

0.0125

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00578

AC:

ESP6500EA

AF:

0.0176

AC:

ExAC

AF:

0.00696

AC:

144

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.0

.;T;.;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.76

T;T;T;T

MetaRNN

Benign

0.0093

T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.7

L;.;L;L

PhyloP100

6.5

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.3

D;.;.;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.012

D;.;.;.

Sift4G

Uncertain

0.024

D;D;D;D

Vest4

0.76

ClinPred

0.017

GERP RS

6.1

Varity_R

0.52

gMVP

0.72

Mutation Taster

=80/20

polymorphism

(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