18-10689746-G-A

Variant names:

• chr18-10689746-G-A
• rs878853137
• NM_001378183.1:c.7406C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378183.1(PIEZO2):​c.7406C>T​(p.Thr2469Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T2469T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 10.0
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• Gordon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• arthrogryposis, distal, with impaired proprioception and touch

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
• arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• connective tissue disorder

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Marden-Walker syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.7406C>T	p.Thr2469Met	missense_variant	Exon 49 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.7406C>T	p.Thr2469Met	missense_variant	Exon 49 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Pathogenic:1

Jun 04, 2014

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Marden-Walker syndrome Uncertain:1

Jun 27, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>T) at position 7067 of the coding sequence of the PIEZO2 gene that results in a threonine to methionine amino acid change at residue 2356 of the piezo type mechanosensitive ion channel component 2 protein. The 2356 residue falls in the anchor domain (PMID: 33422128) which contributes to the maintence of PIEZO2's ion conducting pore. This is a previously reported variant (ClinVar 235840) that has been observed to segregate with distal arthrogryposis type 5 across 4 individuals in a 3 generation pedigree (PMID: 24726473); all affected individuals had contractures of the hands and feet, ptosis, and ophthalmoplegia. In addition, this variant was detected in an uffected individual during preconception screening (PMID: 31589614). This variant is absent from the gnomAD population database (0 of approximately 250,000 alleles). Multiple bioinformatic tools predict that this threonine to methionine amino acid change would be damaging, and the threonine residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP1, PP3 -

not provided Uncertain:1

Jun 26, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 27245685, 30988732, 26008989, 36588752, 24726473, 27743844, 33060286, 30285720, 26259784, 33610426, 32153140) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	.;D;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.3	M;.;.;M
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D;.;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.98
MutPred		0.39		Gain of catalytic residue at T2356 (P = 0.0193);.;.;Gain of catalytic residue at T2356 (P = 0.0193);
MVP		0.87
MPC		0.66
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878853137; hg19: chr18-10689744; COSMIC: COSV53286754;