18-11095365-A-G

Variant names:

• chr18-11095365-A-G
• rs9956571
• NM_001378183.1:c.65-29143T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378183.1(PIEZO2):​c.65-29143T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 152,002 control chromosomes in the GnomAD database, including 10,053 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (10053 hom., cov: 32)
• Consequence: PIEZO2 NM_001378183.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.455
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.65-29143T>C		intron	N/A	NP_001365112.1
	PIEZO2	NM_001410871.1		c.65-29143T>C		intron	N/A	NP_001397800.1
	PIEZO2	NM_022068.4		c.65-29143T>C		intron	N/A	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.65-29143T>C		intron	N/A	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.65-29143T>C		intron	N/A	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.65-29143T>C		intron	N/A	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52275 AN: 151884 Hom.: 10048 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.300

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.344 AC: 52312 AN: 152002 Hom.: 10053 Cov.: 32 AF XY: 0.343 AC XY: 25494 AN XY: 74280

African (AFR) AF: 0.525 AC: 21771 AN: 41446

American (AMR) AF: 0.304 AC: 4648 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3472

East Asian (EAS) AF: 0.235 AC: 1211 AN: 5158

South Asian (SAS) AF: 0.169 AC: 812 AN: 4816

European-Finnish (FIN) AF: 0.328 AC: 3458 AN: 10556

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.269 AC: 18302 AN: 67980

Other (OTH) AF: 0.300 AC: 633 AN: 2110

Alfa AF: 0.283 Hom.: 1264

Bravo AF: 0.351

Asia WGS AF: 0.227 AC: 789 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.2
DANN	Benign	0.27
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs9956571; hg19: chr18-11095364;