chr18-10789114-T-C

Position:

• chr18-10789114-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001378183.1(PIEZO2):​c.2134A>G​(p.Met712Val) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M712I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.67

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 18-10789114-T-C is Pathogenic according to our data. Variant chr18-10789114-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 137633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10789114-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.2134A>G	p.Met712Val	missense_variant	15/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.2134A>G	p.Met712Val	missense_variant	15/56		NM_001378183.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arthrogryposis- oculomotor limitation-electroretinal anomalies 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	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 17, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26259784, 27743844, 30988732, 24726473, 15103714) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.098	.;T;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.3	M;.;M;M
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;.;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0080	D;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D
Vest4		0.83
MutPred		0.40		Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.52
MPC		1.0
ClinPred		0.85	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.78

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: rs587777453; hg19: chr18-10789112;