rs587777076

Variant names:

• chr18-10784872-T-A
• rs587777076
• NM_001378183.1:c.2404A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.61

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 Uncertain_significance. Variant got 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 id is 96704.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-10784872-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.2404A>T	p.Ile802Phe	missense_variant	Exon 17 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.2404A>T	p.Ile802Phe	missense_variant	Exon 17 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Pathogenic:1

Mar 19, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Benign	0.94
DEOGEN2	Benign	0.22	.;T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.0	M;.;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;.;.;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.84
MutPred		0.39		Loss of stability (P = 0.1961);.;Loss of stability (P = 0.1961);Loss of stability (P = 0.1961);
MVP		0.40
MPC		1.3
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.71

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: rs587777076; hg19: chr18-10784870;