chr18-10691359-G-A

Variant names:

• chr18-10691359-G-A
• rs3748421
• NM_001378183.1:c.7215C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):​c.7215C>T​(p.Ala2405Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,610,936 control chromosomes in the GnomAD database, including 88,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6284 hom., cov: 31)
  • Exomes 𝑓: 0.33 (82265 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.584
• Publications: 17 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 18-10691359-G-A is Benign according to our data. Variant chr18-10691359-G-A is described in ClinVar as Benign. ClinVar VariationId is 261526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.584 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.35 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.7215C>T	p.Ala2405Ala	synonymous	Exon 48 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.6951C>T	p.Ala2317Ala	synonymous	Exon 46 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.6876C>T	p.Ala2292Ala	synonymous	Exon 44 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.7215C>T	p.Ala2405Ala	synonymous	Exon 48 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.6876C>T	p.Ala2292Ala	synonymous	Exon 44 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.6951C>T	p.Ala2317Ala	synonymous	Exon 46 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41579 AN: 151860 Hom.: 6282 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.288

GnomAD2 exomes AF: 0.282 AC: 70105 AN: 248420 AF XY: 0.289

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.298

GnomAD4 exome AF: 0.330 AC: 480888 AN: 1458956 Hom.: 82265 Cov.: 35 AF XY: 0.329 AC XY: 238437 AN XY: 725722

African (AFR) AF: 0.151 AC: 5021 AN: 33360

American (AMR) AF: 0.184 AC: 8186 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 9021 AN: 26078

East Asian (EAS) AF: 0.137 AC: 5427 AN: 39508

South Asian (SAS) AF: 0.260 AC: 22282 AN: 85700

European-Finnish (FIN) AF: 0.322 AC: 17171 AN: 53368

Middle Eastern (MID) AF: 0.278 AC: 1600 AN: 5758

European-Non Finnish (NFE) AF: 0.354 AC: 393552 AN: 1110524

Other (OTH) AF: 0.309 AC: 18628 AN: 60278

GnomAD4 genome AF: 0.274 AC: 41589 AN: 151980 Hom.: 6284 Cov.: 31 AF XY: 0.270 AC XY: 20066 AN XY: 74248

African (AFR) AF: 0.159 AC: 6587 AN: 41456

American (AMR) AF: 0.238 AC: 3628 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1233 AN: 3470

East Asian (EAS) AF: 0.108 AC: 560 AN: 5166

South Asian (SAS) AF: 0.238 AC: 1150 AN: 4822

European-Finnish (FIN) AF: 0.323 AC: 3405 AN: 10532

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24049 AN: 67964

Other (OTH) AF: 0.285 AC: 601 AN: 2110

Alfa AF: 0.313 Hom.: 6185

Bravo AF: 0.259

Asia WGS AF: 0.170 AC: 595 AN: 3478

EpiCase AF: 0.353

EpiControl AF: 0.343

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 30, 2019

GeneDx

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gordon syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Marden-Walker syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arthrogryposis, distal, with impaired proprioception and touch Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

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	-0.43
CADD	Benign	4.0
DANN	Benign	0.80
PhyloP100		0.58
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs3748421; hg19: chr18-10691357; COSMIC: COSV53286736;