chr18-10671730-G-A

Position:

• chr18-10671730-G-A

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/exons	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.8395C>T	p.Arg2799Cys	missense_variant	56/56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.8395C>T	p.Arg2799Cys	missense_variant	56/56		NM_001378183.1	ENSP00000501957

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

Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Jun 04, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -

Gordon syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2022

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
MutationTaster	Benign	1.0	D;D;D;D;D
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;