18-10758025-G-T

Variant names:

• chr18-10758025-G-T
• rs7407105
• NM_001378183.1:c.3867C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378183.1(PIEZO2):​c.3867C>A​(p.Asn1289Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1289N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 16 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3353016).

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.3867C>A	p.Asn1289Lys	missense	Exon 27 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.3867C>A	p.Asn1289Lys	missense	Exon 27 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.3792C>A	p.Asn1264Lys	missense	Exon 25 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.3867C>A	p.Asn1289Lys	missense	Exon 27 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.3792C>A	p.Asn1264Lys	missense	Exon 25 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.3867C>A	p.Asn1289Lys	missense	Exon 27 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 6529

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.078
Sift	Benign	0.22	T
Sift4G	Uncertain	0.048	D
Polyphen		0.16	B
Vest4		0.34
MutPred		0.48		Gain of ubiquitination at N1264 (P = 0.0219)
MVP		0.043
MPC		0.41
ClinPred		0.53	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.37
Mutation Taster		=58/42	polymorphism

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: rs7407105; hg19: chr18-10758023;