rs878853137

Variant names:

• chr18-10689746-G-A
• rs878853137
• NM_001378183.1:c.7406C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378183.1(PIEZO2):​c.7406C>T​(p.Thr2469Met) 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. 14/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T2469T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 10.0
• Publications: 9 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• arthrogryposis, distal, with impaired proprioception and touch

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• connective tissue disorder

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Marden-Walker syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics

ACMG classification

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, 0.919

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.7406C>T	p.Thr2469Met	missense	Exon 49 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.7142C>T	p.Thr2381Met	missense	Exon 47 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.7067C>T	p.Thr2356Met	missense	Exon 45 of 52	NP_071351.2	Q9H5I5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.7406C>T	p.Thr2469Met	missense	Exon 49 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.7067C>T	p.Thr2356Met	missense	Exon 45 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.7142C>T	p.Thr2381Met	missense	Exon 47 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome (1)
-	1	-	Marden-Walker syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.98
MutPred		0.39		Gain of catalytic residue at T2356 (P = 0.0193)
MVP		0.87
MPC		0.66
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878853137; hg19: chr18-10689744; COSMIC: COSV53286754;