16-88715610-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001142864.4(PIEZO1):ā€‹c.7561G>Cā€‹(p.Glu2521Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000189 in 1,549,802 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0010 ( 0 hom., cov: 33)
Exomes š‘“: 0.00010 ( 1 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

5
14

Clinical Significance

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

Conservation

PhyloP100: 3.85
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 Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.00760749).
BP6
Variant 16-88715610-C-G is Benign according to our data. Variant chr16-88715610-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2041916.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
BS2
High AC in GnomAd4 at 153 AD,BG gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PIEZO1NM_001142864.4 linkuse as main transcriptc.7561G>C p.Glu2521Gln missense_variant 51/51 ENST00000301015.14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PIEZO1ENST00000301015.14 linkuse as main transcriptc.7561G>C p.Glu2521Gln missense_variant 51/511 NM_001142864.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00101
AC:
154
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000230
AC:
35
AN:
152432
Hom.:
0
AF XY:
0.000185
AC XY:
15
AN XY:
81242
show subpopulations
Gnomad AFR exome
AF:
0.00310
Gnomad AMR exome
AF:
0.000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000173
Gnomad OTH exome
AF:
0.000232
GnomAD4 exome
AF:
0.000100
AC:
140
AN:
1397508
Hom.:
1
Cov.:
32
AF XY:
0.0000827
AC XY:
57
AN XY:
689220
show subpopulations
Gnomad4 AFR exome
AF:
0.00339
Gnomad4 AMR exome
AF:
0.000364
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000371
Gnomad4 OTH exome
AF:
0.000276
GnomAD4 genome
AF:
0.00100
AC:
153
AN:
152294
Hom.:
0
Cov.:
33
AF XY:
0.000873
AC XY:
65
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00358
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000347
Hom.:
0
Bravo
AF:
0.00116
ExAC
AF:
0.000197
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 03, 2022The c.7561G>C (p.E2521Q) alteration is located in exon 51 (coding exon 51) of the PIEZO1 gene. This alteration results from a G to C substitution at nucleotide position 7561, causing the glutamic acid (E) at amino acid position 2521 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0074
T
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.0076
T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.9
N
REVEL
Benign
0.17
Sift
Benign
0.097
T
Sift4G
Benign
0.21
T
Polyphen
0.37
B
Vest4
0.28
MVP
0.18
ClinPred
0.021
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.17
gMVP
0.51

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: rs73262683; hg19: chr16-88782018; API