rs76488076

Variant names:

• chr18-10787128-A-C
• rs76488076
• NM_001378183.1:c.2226T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-10787128-A-C
• chr18-10787128-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000674853.1(PIEZO2):​c.2226T>G​(p.Ile742Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. I742I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PIEZO2 ENST00000674853.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00600
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• arthrogryposis, distal, with impaired proprioception and touch

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

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

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22259504).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000674853.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.2226T>G	p.Ile742Met	missense	Exon 16 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.2226T>G	p.Ile742Met	missense	Exon 16 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.2226T>G	p.Ile742Met	missense	Exon 16 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.2226T>G	p.Ile742Met	missense	Exon 16 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.2226T>G	p.Ile742Met	missense	Exon 16 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.2226T>G	p.Ile742Met	missense	Exon 16 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383478 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 682654

African (AFR) AF: 0.00 AC: 0 AN: 31542

American (AMR) AF: 0.00 AC: 0 AN: 35558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35680

South Asian (SAS) AF: 0.00 AC: 0 AN: 78944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1078104

Other (OTH) AF: 0.00 AC: 0 AN: 57856

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.0060
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.071
Sift	Benign	0.057	T
Sift4G	Uncertain	0.013	D
Vest4		0.32
MutPred		0.51		Loss of catalytic residue at I742 (P = 0.0041)
MVP		0.18
MPC		0.33
ClinPred		0.049	T
GERP RS		0.27
Varity_R		0.067
gMVP		0.24
Mutation Taster		=77/23	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: rs76488076; hg19: chr18-10787126;