18-10789114-T-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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 Pathogenic (★★).

• 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

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 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]. Clinvar id is 137633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10789114-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.2134A>G	p.Met712Val	missense_variant	Exon 15 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.2134A>G	p.Met712Val	missense_variant	Exon 15 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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. -

May 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 04, 2014

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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 v4.3

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;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.3	M;.;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;.;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0080	D;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D
Vest4		0.83
MutPred		0.40		Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);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

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: rs587777453; hg19: chr18-10789112;