chr16-88715666-T-C

Variant names:

Variant summary

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

The NM_001142864.4(PIEZO1):c.7505A>G(p.Lys2502Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00581 in 1,550,310 control chromosomes in the GnomAD database, including 50 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 0.0057 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 48 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 7.84

Publications

11 publications found

Variant links:

Genes affected

PIEZO1 (HGNC:28993): (piezo type mechanosensitive ion channel component 1 (Er blood group)) The protein encoded by this gene is a mechanically-activated ion channel that links mechanical forces to biological signals. The encoded protein contains 36 transmembrane domains and functions as a homotetramer. Defects in this gene have been associated with dehydrated hereditary stomatocytosis. [provided by RefSeq, Jul 2015]

PIEZO1 Gene-Disease associations (from GenCC):

PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema
Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
lymphatic malformation 6
Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
dehydrated hereditary stomatocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIEZO1 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=0.009955108).

BP6

Variant 16-88715666-T-C is Benign according to our data. Variant chr16-88715666-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 710278.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00566 (862/152322) while in subpopulation NFE AF = 0.00598 (407/68022). AF 95% confidence interval is 0.0055. There are 2 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142864.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	NM_001142864.4	MANE Select	c.7505A>G	p.Lys2502Arg	missense	Exon 51 of 51	NP_001136336.2	Q92508

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.7505A>G	p.Lys2502Arg	missense	Exon 51 of 51	ENSP00000301015.9	Q92508
PIEZO1	ENST00000419505.5	TSL:1	n.*1045A>G		non_coding_transcript_exon	Exon 10 of 10	ENSP00000406358.1	H7C2J5
PIEZO1	ENST00000419505.5	TSL:1	n.*1045A>G		3_prime_UTR	Exon 10 of 10	ENSP00000406358.1	H7C2J5

Frequencies

GnomAD3 genomes

AF:

0.00566

AC:

862

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0330

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00598

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00608

AC:

946

AN:

155478

AF XY:

0.00544

show subpopulations

Gnomad AFR exome

AF:

0.000382

Gnomad AMR exome

AF:

0.00312

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00480

GnomAD4 exome

AF:

0.00583

AC:

8144

AN:

1397988

Hom.:

Cov.:

AF XY:

0.00562

AC XY:

3878

AN XY:

689490

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

31596

American (AMR)

AF:

0.00274

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.000252

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.0291

AC:

1395

AN:

47944

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00583

AC:

6285

AN:

1078910

Other (OTH)

AF:

0.00478

AC:

277

AN:

57984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

467

934

1400

1867

2334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

238

476

714

952

1190

<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:

0.00566

AC:

862

AN:

152322

Hom.:

Cov.:

AF XY:

0.00654

AC XY:

487

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41576

American (AMR)

AF:

0.00431

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0330

AC:

350

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00598

AC:

407

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

127

170

212

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:

0.00461

Hom.:

Bravo

AF:

0.00283

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00467

AC:

ExAC

AF:

0.00392

AC:

103

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (1)

PIEZO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.010

MutationAssessor

Uncertain

2.8

PhyloP100

7.8

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.55

MVP

0.36

ClinPred

0.035

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.76

Mutation Taster

=49/51

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