rs587777451

Variant names:

• chr18-10671730-G-A
• rs587777451
• NM_001378183.1:c.8395C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-10671730-G-A
• chr18-10671730-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001378183.1(PIEZO2):​c.8395C>T​(p.Arg2799Cys) 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. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2799H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.96

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-10671729-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 18-10671730-G-A is Pathogenic according to our data. Variant chr18-10671730-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 137630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10671730-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.8395C>T	p.Arg2799Cys	missense_variant	Exon 56 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.8395C>T	p.Arg2799Cys	missense_variant	Exon 56 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marden-Walker syndrome Pathogenic:2

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

- -

Gordon syndrome Pathogenic:1

Sep 01, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PIEZO2 -related disorder (ClinVar ID: VCV000137630 / PMID: 24726473). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 24726473). Different missense changes at the same codon (p.Arg2799Gly, p.Arg2799His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000137629 , VCV000973945). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Nov 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24726473, 33726816, 35627109) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;D;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.4	.;.;.;M
PrimateAI	Pathogenic	0.88	D
REVEL	Pathogenic	0.97
Sift4G	Uncertain	0.0060	D;D;D;D
Vest4		0.88
MVP		0.18
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.81
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs587777451; hg19: chr18-10671727;