18-10789114-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_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

Scores

7
8
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.67
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]

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ACMG classification

Classification made for transcript

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
PIEZO2NM_001378183.1 linkc.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
PIEZO2ENST00000674853.1 linkc.2134A>G p.Met712Val missense_variant Exon 15 of 56 NM_001378183.1 ENSP00000501957.1 A0A2H4UKA7

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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777453; hg19: chr18-10789112; API