Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001378183.1(PIEZO2):c.2404A>T(p.Ile802Phe) 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 (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.61

Publications

13 publications found

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]

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

PIEZO2 links:

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ACMG classification

Classification was made for transcript

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, 0.779

PP5

Variant 18-10784872-T-A is Pathogenic according to our data. Variant chr18-10784872-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 96704.Status of the report is no_assertion_criteria_provided, 0 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIEZO2	NM_001378183.1	MANE Select	c.2404A>T	p.Ile802Phe	missense	Exon 17 of 56	NP_001365112.1
PIEZO2	NM_001410871.1		c.2404A>T	p.Ile802Phe	missense	Exon 17 of 54	NP_001397800.1
PIEZO2	NM_022068.4		c.2404A>T	p.Ile802Phe	missense	Exon 17 of 52	NP_071351.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIEZO2	ENST00000674853.1	MANE Select	c.2404A>T	p.Ile802Phe	missense	Exon 17 of 56	ENSP00000501957.1
PIEZO2	ENST00000503781.7	TSL:1	c.2404A>T	p.Ile802Phe	missense	Exon 17 of 52	ENSP00000421377.3
PIEZO2	ENST00000580640.5	TSL:5	c.2404A>T	p.Ile802Phe	missense	Exon 17 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.22

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.86

MutationAssessor

Pathogenic

3.0

PhyloP100

7.6

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.84

MutPred

0.39

Loss of stability (P = 0.1961)

MVP

0.40

MPC

1.3

ClinPred

0.98

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.71

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over