16-88715666-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 710278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr16-88715666-T-C is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 862 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4 link	c.7505A>G	p.Lys2502Arg	missense_variant	Exon 51 of 51	ENST00000301015.14	NP_001136336.2	Q92508

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14 link	c.7505A>G	p.Lys2502Arg	missense_variant	Exon 51 of 51	1	NM_001142864.4	ENSP00000301015.9		Q92508

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

GnomAD3 exomes

AF:

0.00608

AC:

946

AN:

155478

Hom.:

AF XY:

0.00544

AC XY:

449

AN XY:

82594

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 SAS exome

AF:

0.000264

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

Gnomad4 AFR exome

AF:

0.000506

Gnomad4 AMR exome

AF:

0.00274

Gnomad4 ASJ exome

AF:

0.00207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000252

Gnomad4 FIN exome

AF:

0.0291

Gnomad4 NFE exome

AF:

0.00583

Gnomad4 OTH exome

AF:

0.00478

GnomAD4 genome

AF:

0.00566

AC:

862

AN:

152322

Hom.:

Cov.:

AF XY:

0.00654

AC XY:

487

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0330

Gnomad4 NFE

AF:

0.00598

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00491

Hom.:

Bravo

AF:

0.00283

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00467

AC:

ExAC

AF:

0.00392

AC:

103

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

May 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BS2 -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIEZO1: BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PIEZO1-related disorder

Benign:1

Apr 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over