18-10704640-G-A

Variant names:

• chr18-10704640-G-A
• rs16975235
• NM_001378183.1:c.6012C>T

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.6012C>T​(p.Asp2004Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,536,402 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (65 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.254
• 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

ENSG00000264843 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-10704640-G-A is Benign according to our data. Variant chr18-10704640-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.254 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 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.6012C>T	p.Asp2004Asp	synonymous	Exon 42 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.5748C>T	p.Asp1916Asp	synonymous	Exon 40 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.5673C>T	p.Asp1891Asp	synonymous	Exon 38 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.6012C>T	p.Asp2004Asp	synonymous	Exon 42 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.5673C>T	p.Asp1891Asp	synonymous	Exon 38 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.5748C>T	p.Asp1916Asp	synonymous	Exon 40 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2281 AN: 152190 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00372 AC: 525 AN: 141116 AF XY: 0.00272

Gnomad AFR exome AF: 0.0556

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.000238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000260

Gnomad OTH exome AF: 0.00143

GnomAD4 exome AF: 0.00169 AC: 2346 AN: 1384094 Hom.: 65 Cov.: 31 AF XY: 0.00149 AC XY: 1019 AN XY: 682798

African (AFR) AF: 0.0561 AC: 1773 AN: 31578

American (AMR) AF: 0.00272 AC: 97 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25178

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35708

South Asian (SAS) AF: 0.000858 AC: 68 AN: 79214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35000

Middle Eastern (MID) AF: 0.00422 AC: 24 AN: 5686

European-Non Finnish (NFE) AF: 0.000189 AC: 204 AN: 1078164

Other (OTH) AF: 0.00306 AC: 177 AN: 57870

GnomAD4 genome AF: 0.0150 AC: 2284 AN: 152308 Hom.: 56 Cov.: 32 AF XY: 0.0145 AC XY: 1078 AN XY: 74468

African (AFR) AF: 0.0522 AC: 2171 AN: 41562

American (AMR) AF: 0.00451 AC: 69 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68026

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00850 Hom.: 10

Bravo AF: 0.0164

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 06, 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

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gordon syndrome;C0796033:Marden-Walker syndrome;C1862472:Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome;C4310692:Arthrogryposis, distal, with impaired proprioception and touch Benign:1

Sep 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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	-0.80
CADD	Benign	0.056
DANN	Benign	0.76
PhyloP100		-0.25
Mutation Taster		=99/1	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: rs16975235; hg19: chr18-10704638; COSMIC: COSV53288290; COSMIC: COSV53288290;