rs886039821

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001378183.1(PIEZO2):c.5227C>T(p.Arg1743Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PIEZO2
NM_001378183.1 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.879

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-10715679-G-A is Pathogenic according to our data. Variant chr18-10715679-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1 linkuse as main transcript	c.5227C>T	p.Arg1743Ter	stop_gained	38/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1 linkuse as main transcript	c.5227C>T	p.Arg1743Ter	stop_gained	38/56		NM_001378183.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1383202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682410

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arthrogryposis, distal, with impaired proprioception and touch

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 03, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 28, 2020	The PIEZO2 c.5053C>T (p.Arg1685Ter) variant is a stop-gained variant that has been reported in one study, in which it is found in a compound heterozygous state in two unrelated individuals with distal arthrogryposis with impaired proprioception and touch (Chesler et al. 2016). The patients presented with congenital hip dysplasia, finger contractures, foot deformities, and progressive scoliosis and had a history of hypotonia, delayed head control, shallow breathing, and delayed walking. Both patients also had selective loss of touch perception and proprioception, leading to ataxia and dysmetria. The p.Arg1685Ter is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. In vitro functional studies showed that p.Arg1685Ter transfected cells had significantly reduced mechanically evoked current, and analysis of PIEZO2 RNA expression in patient cells implied the variant leads to nonsense-mediated decay (Chesler et al. 2016). Based on the collective evidence and application of the ACMG criteria, the p.Arg1685Ter variant is classified as pathogenic for distal arthrogryposis with impaired proprioception and touch. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2019	A nonsense variant that is likely pathogenic has been identified in the PIEZO2 gene. The R1685X variant has been previously reported in two unrelated individuals, each harboring a second PIEZO2 variant, with congenital hip dysplasia, finger contractures, foot deformities, severe progressive scoliosis, hypotonia, delayed walking, ataxia, selective loss of discriminative touch perception, and impaired fine motor skills (Chesler et al., 2016). Functional studies showed that R1685X transfected cells had channel currents above baseline noise only, compared to wild type, supporting loss of function (Chesler et al., 2016). The R1685X variant is not observed in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 16, 2022	This sequence change creates a premature translational stop signal (p.Arg1685*) in the PIEZO2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIEZO2 are known to be pathogenic (PMID: 27653382, 27843126). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 265867). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive distal arthrogryposis (PMID: 27653382). This variant is not present in population databases (gnomAD no frequency). -

PIEZO2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 29, 2024

Variant summary: PIEZO2 c.5053C>T (p.Arg1685X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.5053C>T has been reported in the literature in two unrelated individuals affected with skeletal malformations, hypotonia, and impaired proprioception who were compound heterozygous with other pathogenic variants (Chesler_2016). This publication reports experimental evidence evaluating an impact on protein function, finding a loss of channel current in cells transfected with the variant protein. The following publication has been ascertained in the context of this evaluation (PMID: 27653382). ClinVar contains an entry for this variant (Variation ID: 265867). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.060

FATHMM_MKL

Benign

0.76

MutationTaster

Benign

1.0

A;A;A

Vest4

0.76

GERP RS

-1.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: -29

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