chr16-88715618-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001142864.4(PIEZO1):ā€‹c.7553G>Cā€‹(p.Arg2518Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000387 in 1,549,824 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2518H) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 33)
Exomes š‘“: 0.000041 ( 1 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

6
11
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.80
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.808
BS2
High AC in GnomAdExome4 at 57 AD,BG gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PIEZO1NM_001142864.4 linkuse as main transcriptc.7553G>C p.Arg2518Pro missense_variant 51/51 ENST00000301015.14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PIEZO1ENST00000301015.14 linkuse as main transcriptc.7553G>C p.Arg2518Pro missense_variant 51/511 NM_001142864.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152184
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000523
AC:
8
AN:
152992
Hom.:
0
AF XY:
0.0000737
AC XY:
6
AN XY:
81462
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000308
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000172
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000408
AC:
57
AN:
1397640
Hom.:
1
Cov.:
32
AF XY:
0.0000580
AC XY:
40
AN XY:
689316
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000328
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000278
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152184
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000255
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.000118
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lymphatic malformation 6 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingClinical Genomics Laboratory, Washington University in St. LouisSep 15, 2023The PIEZO1 c.7553G>C (p.Arg2518Pro) variant was identified at a near-heterozygous allelic fraction. This variant, to our knowledge, has not been reported in the medical literature. This variant has been reported in the ClinVar database as a variant of uncertain significance by two submitters (ClinVar ID: 638426). This variant is only observed on 3/152184 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on the PIEZO1 function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesApr 27, 2019- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Benign
-0.053
T
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.62
D
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.86
D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.81
D
MetaSVM
Uncertain
0.21
D
MutationAssessor
Pathogenic
3.1
M
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-6.2
D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0040
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.61
MutPred
0.43
Loss of MoRF binding (P = 6e-04);
MVP
0.43
ClinPred
0.89
D
GERP RS
3.8
Varity_R
0.80
gMVP
0.94

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.

Other links and lift over

dbSNP: rs774268616; hg19: chr16-88782026; API