Variant chr18-10671602-ATCT-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_001378183.1(PIEZO2):c.8520_8522delAGA(p.Glu2840del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000137 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PIEZO2
NM_001378183.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.19

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001378183.1. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 18-10671602-ATCT-A is Pathogenic according to our data. Variant chr18-10671602-ATCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 235839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10671602-ATCT-A is described in Lovd as [Pathogenic]. Variant chr18-10671602-ATCT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.8520_8522delAGA	p.Glu2840del	disruptive_inframe_deletion	Exon 56 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1 link	c.8520_8522delAGA	p.Glu2840del	disruptive_inframe_deletion	Exon 56 of 56		NM_001378183.1	ENSP00000501957.1		A0A2H4UKA7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152210

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

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0.00

Gnomad ASJ

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0.00

Gnomad EAS

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0.00

Gnomad SAS

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0.00

Gnomad FIN

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0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461648

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727140

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

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0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

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0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Oct 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect on ion channel inactivation, as human cells with the E2727del variant had slower inactivation and faster recovery in response to a mechanical stimulus, suggesting a gain-of-function effect (Coste et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26259784, 24532247, 23487782, 31965297, 30131872, 31230720, 28974772, 30169785, 27743844, 30988732, 28636944, 35906671, 35698866, 34203046, 11146470, 17345626, Ma2022[Preprint], 27535533, 24726473) -

Dec 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inframe deletion variant c.8520_8522del (p.Glu2840del) in PIEZO2 gene has been reported previously as a de novo variant in multiple individuals with distal arthrogryposis type 5 (Coste et al., 2013; McMillin et al, 2014). Functional studies demonstrate that the c.8181_8183delAGA variant is associated with increased channel activity in response to repetitive mechanical signals (Coste et al., 2013).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu2840del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This p.Glu2840del causes deletion of amino acid Glutamic Acid at position 2840. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 04, 2014

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Gordon syndrome

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases

Pathogenic:1

Jun 18, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8181_8183delAGA (p.E2727del) alteration, located in exon coding 52 of the PIEZO2 gene, results from an in-frame deletion at nucleotide positions c.8181 to c.8183. This results in the deletion of a glutamic acid residue at codon p.2727. for autosomal dominant PIEZO2-related distal arthrogryposis; however, its clinical significance for autosomal recessive PIEZO2-related distal arthrogryposis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with autosomal dominant PIEZO2-related distal arthrogryposis. It has also been shown to segregate with disease in affected families (Coste, 2013; McMillin, 2014). This amino acid position is highly conserved in available vertebrate species. In an electrophysiological study, this variant showed a functionally abnormal result (Coste, 2013). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Distal arthrogryposis

Pathogenic:1

May 16, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

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Splicing

Name

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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