18-10704450-A-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_001378183.1(PIEZO2):c.6202T>A(p.Leu2068Met) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,537,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L2068L) has been classified as Benign.
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 1 hom. )
Consequence
PIEZO2
NM_001378183.1 missense
NM_001378183.1 missense
Scores
3
6
10
Clinical Significance
Conservation
PhyloP100: 3.87
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 Likely_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.4093642).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIEZO2 | NM_001378183.1 | c.6202T>A | p.Leu2068Met | missense_variant | 42/56 | ENST00000674853.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIEZO2 | ENST00000674853.1 | c.6202T>A | p.Leu2068Met | missense_variant | 42/56 | NM_001378183.1 | |||
ENST00000584167.1 | n.37+117A>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152170Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000134 AC: 19AN: 141888Hom.: 1 AF XY: 0.000119 AC XY: 9AN XY: 75888
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GnomAD4 exome AF: 0.000233 AC: 323AN: 1384940Hom.: 1 Cov.: 30 AF XY: 0.000222 AC XY: 152AN XY: 683400
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GnomAD4 genome AF: 0.000177 AC: 27AN: 152288Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74470
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 15, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2022 | The c.5863T>A (p.L1955M) alteration is located in exon 38 (coding exon 38) of the PIEZO2 gene. This alteration results from a T to A substitution at nucleotide position 5863, causing the leucine (L) at amino acid position 1955 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1955 of the PIEZO2 protein (p.Leu1955Met). This variant is present in population databases (rs112982077, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with PIEZO2-related conditions. ClinVar contains an entry for this variant (Variation ID: 436312). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIEZO2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
.;T;.;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;.;.;.
REVEL
Benign
Sift
Pathogenic
D;.;.;.
Sift4G
Uncertain
D;D;D;D
Vest4
MutPred
Gain of catalytic residue at L1955 (P = 0.0387);.;.;Gain of catalytic residue at L1955 (P = 0.0387);
MVP
MPC
1.0
ClinPred
T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at