chr18-10855553-C-T

Variant names:

• chr18-10855553-C-T
• rs8085615
• NM_001378183.1:c.717G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):​c.717G>A​(p.Pro239Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00587 in 1,536,356 control chromosomes in the GnomAD database, including 428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (225 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (203 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.599
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 18-10855553-C-T is Benign according to our data. Variant chr18-10855553-C-T is described in ClinVar as Benign. ClinVar VariationId is 261529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.599 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 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.717G>A	p.Pro239Pro	synonymous	Exon 7 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.717G>A	p.Pro239Pro	synonymous	Exon 7 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.717G>A	p.Pro239Pro	synonymous	Exon 7 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.717G>A	p.Pro239Pro	synonymous	Exon 7 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.717G>A	p.Pro239Pro	synonymous	Exon 7 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.717G>A	p.Pro239Pro	synonymous	Exon 7 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4619 AN: 152084 Hom.: 223 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.00727 AC: 1025 AN: 141002 AF XY: 0.00555

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00556

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00381

GnomAD4 exome AF: 0.00317 AC: 4386 AN: 1384154 Hom.: 203 Cov.: 31 AF XY: 0.00270 AC XY: 1846 AN XY: 682962

African (AFR) AF: 0.107 AC: 3364 AN: 31556

American (AMR) AF: 0.00670 AC: 239 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.000834 AC: 21 AN: 25180

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35730

South Asian (SAS) AF: 0.000202 AC: 16 AN: 79208

European-Finnish (FIN) AF: 0.0000865 AC: 3 AN: 34678

Middle Eastern (MID) AF: 0.00738 AC: 42 AN: 5694

European-Non Finnish (NFE) AF: 0.000243 AC: 262 AN: 1078510

Other (OTH) AF: 0.00751 AC: 435 AN: 57902

GnomAD4 genome AF: 0.0304 AC: 4627 AN: 152202 Hom.: 225 Cov.: 32 AF XY: 0.0293 AC XY: 2178 AN XY: 74400

African (AFR) AF: 0.105 AC: 4368 AN: 41506

American (AMR) AF: 0.0102 AC: 156 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68016

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0104 Hom.: 17

Bravo AF: 0.0343

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.5
DANN	Benign	0.85
PhyloP100		-0.60
PromoterAI		0.031	Neutral
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8085615; hg19: chr18-10855551; COSMIC: COSV57437416; COSMIC: COSV57437416;