18-10695563-T-C

Variant names:

• chr18-10695563-T-C
• rs11660953
• NM_001378183.1:c.7190+511A>G

Variant summary

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

The NM_001378183.1(PIEZO2):​c.7190+511A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 151,960 control chromosomes in the GnomAD database, including 9,874 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 0.36 (9874 hom., cov: 31)
• Consequence: PIEZO2 NM_001378183.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.379 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.7190+511A>G		intron	N/A	NP_001365112.1
	PIEZO2	NM_001410871.1		c.6926+511A>G		intron	N/A	NP_001397800.1
	PIEZO2	NM_022068.4		c.6851+511A>G		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.7190+511A>G		intron	N/A	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.6851+511A>G		intron	N/A	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.6926+511A>G		intron	N/A	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54735 AN: 151842 Hom.: 9869 Cov.: 31

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.366

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

GnomAD4 genome AF: 0.360 AC: 54756 AN: 151960 Hom.: 9874 Cov.: 31 AF XY: 0.357 AC XY: 26535 AN XY: 74274

African (AFR) AF: 0.355 AC: 14708 AN: 41460

American (AMR) AF: 0.318 AC: 4861 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1362 AN: 3468

East Asian (EAS) AF: 0.308 AC: 1585 AN: 5140

South Asian (SAS) AF: 0.263 AC: 1267 AN: 4822

European-Finnish (FIN) AF: 0.362 AC: 3824 AN: 10570

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26001 AN: 67930

Other (OTH) AF: 0.363 AC: 762 AN: 2102

Alfa AF: 0.362 Hom.: 1650

Bravo AF: 0.355

Asia WGS AF: 0.265 AC: 926 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.55
PhyloP100		-1.0
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: rs11660953; hg19: chr18-10695561;