Genetic Variant PIEZO2:p.Ala2657Thr (chr18-10677859-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378183.1(PIEZO2):c.7969G>A(p.Ala2657Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,590,704 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 6 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 6.37

Publications

1 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: Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038327932).

BP6

Variant 18-10677859-C-T is Benign according to our data. Variant chr18-10677859-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445793.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00112 (165/147884) while in subpopulation NFE AF = 0.00169 (113/67058). AF 95% confidence interval is 0.00143. There are 1 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

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.7969G>A	p.Ala2657Thr	missense	Exon 53 of 56	NP_001365112.1	A0A2H4UKA7
PIEZO2	NM_001410871.1		c.7705G>A	p.Ala2569Thr	missense	Exon 51 of 54	NP_001397800.1	Q9H5I5-4
PIEZO2	NM_022068.4		c.7630G>A	p.Ala2544Thr	missense	Exon 49 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.7969G>A	p.Ala2657Thr	missense	Exon 53 of 56	ENSP00000501957.1	A0A2H4UKA7
PIEZO2	ENST00000503781.7	TSL:1	c.7630G>A	p.Ala2544Thr	missense	Exon 49 of 52	ENSP00000421377.3	Q9H5I5-1
PIEZO2	ENST00000580640.5	TSL:5	c.7705G>A	p.Ala2569Thr	missense	Exon 51 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

165

AN:

147766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000902

Gnomad ASJ

AF:

0.00585

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000224

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00327

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.000503

GnomAD2 exomes

AF:

0.00106

AC:

239

AN:

226266

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.000512

Gnomad AMR exome

AF:

0.000540

Gnomad ASJ exome

AF:

0.00609

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.00129

AC:

1868

AN:

1442820

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

924

AN XY:

717126

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

32104

American (AMR)

AF:

0.000655

AC:

AN:

39692

Ashkenazi Jewish (ASJ)

AF:

0.00479

AC:

123

AN:

25668

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.000270

AC:

AN:

81342

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52098

Middle Eastern (MID)

AF:

0.00125

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

0.00146

AC:

1613

AN:

1107046

Other (OTH)

AF:

0.00116

AC:

AN:

59722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

161

241

322

402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00112

AC:

165

AN:

147884

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

AN XY:

71898

show subpopulations

African (AFR)

AF:

0.000397

AC:

AN:

40342

American (AMR)

AF:

0.000901

AC:

AN:

14430

Ashkenazi Jewish (ASJ)

AF:

0.00585

AC:

AN:

3420

East Asian (EAS)

AF:

0.00

AC:

AN:

4944

South Asian (SAS)

AF:

0.000224

AC:

AN:

4460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10046

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00169

AC:

113

AN:

67058

Other (OTH)

AF:

0.000498

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00140

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000840

AC:

102

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00219

EpiControl

AF:

0.00192

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

Inborn genetic diseases (1)

PIEZO2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.038

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.8

PhyloP100

6.4

PrimateAI

Uncertain

0.51

REVEL

Uncertain

0.40

Sift4G

Uncertain

0.031

Vest4

0.74

MVP

0.043

MPC

0.89

ClinPred

0.035

GERP RS

5.6

Varity_R

0.27

gMVP

0.38

Mutation Taster

=46/54

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over