18-10789114-T-C

Variant names:

• chr18-10789114-T-C
• rs587777453
• NM_001378183.1:c.2134A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001378183.1(PIEZO2):​c.2134A>G​(p.Met712Val) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M712I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.67
• Publications: 5 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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 18-10789114-T-C is Pathogenic according to our data. Variant chr18-10789114-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 137633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378183.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.2134A>G	p.Met712Val	missense	Exon 15 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.2134A>G	p.Met712Val	missense	Exon 15 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.2134A>G	p.Met712Val	missense	Exon 15 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.2134A>G	p.Met712Val	missense	Exon 15 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.2134A>G	p.Met712Val	missense	Exon 15 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.2134A>G	p.Met712Val	missense	Exon 15 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Pathogenic:3

Aug 01, 2024

Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.2134A>G, p.Met712Val, variant found is located in exon 15 of the PIEZO2 gene. The variant found was reported de novo in a patient with no family history (ClinVar ID: 137633) (PS2). The variant found is not present in population-based databases such as GnomAD, ExAc, or 1000 Genomes (PM2_Supporting). In the PIEZO2 gene, missense variants are a frequent cause of pathology (PP2). Bioinformatics predictors classify the variant as deleted (PP3). The patient's phenotype is consistent with distal arthrogryposis type 5, and the PIEZO2 gene is closely associated with the pathology (PP4). A 21-year-old patient was being studied for suspected distal arthrogryposis. The patient presents short stature, arthrogryposis, campodactyly, clinodactyly, limited wrist extension, enophthalmos, and bilateral eyelid ptosis.

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

Inborn genetic diseases Pathogenic:1

Dec 14, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Dec 17, 2023

GeneDx

Significance: Pathogenic

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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26259784, 27743844, 30988732, 24726473, 15103714)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0050	D
Vest4		0.83
MutPred		0.40		Gain of sheet (P = 0.039)
MVP		0.52
MPC		1.0
ClinPred		0.85	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.78
Mutation Taster		=6/94	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: rs587777453; hg19: chr18-10789112;