chr18-10671602-ATCT-A

Variant names:

• chr18-10671602-ATCT-A
• rs1555621138
• NM_001378183.1:c.8520_8522delAGA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.19

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]

ACMG classification

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	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	c.8520_8522delAGA	p.Glu2840del	disruptive_inframe_deletion	Exon 56 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152210 Hom.: 0 Cov.: 32 FAILED QC

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461648 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727140

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: 0 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Jun 04, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

Gordon syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 16, 2014

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1555621138; hg19: chr18-10671599;