rs35033671

Variant names:

• chr18-10759842-C-A
• rs35033671
• NM_001378183.1:c.3518G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378183.1(PIEZO2):​c.3518G>T​(p.Cys1173Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,537,210 control chromosomes in the GnomAD database, including 31,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1173S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2561 hom., cov: 32)
  • Exomes 𝑓: 0.20 (28947 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.55
• Publications: 23 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]

MIR6788 (HGNC:50078): (microRNA 6788) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017485023).
• BP6: Variant 18-10759842-C-A is Benign according to our data. Variant chr18-10759842-C-A is described in ClinVar as Benign. ClinVar VariationId is 261506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.232 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.3518G>T	p.Cys1173Phe	missense	Exon 25 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.3518G>T	p.Cys1173Phe	missense	Exon 25 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.3443G>T	p.Cys1148Phe	missense	Exon 23 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.3518G>T	p.Cys1173Phe	missense	Exon 25 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.3443G>T	p.Cys1148Phe	missense	Exon 23 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.3518G>T	p.Cys1173Phe	missense	Exon 25 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24737 AN: 152072 Hom.: 2562 Cov.: 32

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0882

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.175

GnomAD2 exomes AF: 0.204 AC: 29685 AN: 145282 AF XY: 0.207

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.0897

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.201 AC: 277759 AN: 1385020 Hom.: 28947 Cov.: 35 AF XY: 0.202 AC XY: 138379 AN XY: 683406

African (AFR) AF: 0.0325 AC: 1027 AN: 31596

American (AMR) AF: 0.270 AC: 9639 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 4069 AN: 25182

East Asian (EAS) AF: 0.0993 AC: 3547 AN: 35734

South Asian (SAS) AF: 0.243 AC: 19287 AN: 79234

European-Finnish (FIN) AF: 0.226 AC: 7912 AN: 35074

Middle Eastern (MID) AF: 0.166 AC: 943 AN: 5696

European-Non Finnish (NFE) AF: 0.204 AC: 220581 AN: 1078842

Other (OTH) AF: 0.186 AC: 10754 AN: 57962

GnomAD4 genome AF: 0.163 AC: 24733 AN: 152190 Hom.: 2561 Cov.: 32 AF XY: 0.164 AC XY: 12203 AN XY: 74392

African (AFR) AF: 0.0391 AC: 1623 AN: 41538

American (AMR) AF: 0.239 AC: 3651 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 530 AN: 3466

East Asian (EAS) AF: 0.0882 AC: 457 AN: 5180

South Asian (SAS) AF: 0.242 AC: 1168 AN: 4822

European-Finnish (FIN) AF: 0.212 AC: 2245 AN: 10566

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14390 AN: 68004

Other (OTH) AF: 0.172 AC: 363 AN: 2110

Alfa AF: 0.187 Hom.: 5576

Bravo AF: 0.157

TwinsUK AF: 0.214 AC: 792

ALSPAC AF: 0.215 AC: 827

ESP6500AA AF: 0.0368 AC: 51

ESP6500EA AF: 0.209 AC: 664

ExAC AF: 0.183 AC: 4344

Asia WGS AF: 0.128 AC: 444 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 28, 2018

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.072
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.12	N
PhyloP100		2.5
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Benign	0.16
Sift	Benign	0.17	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.22
MPC		0.46
ClinPred		0.031	T
GERP RS		5.0
Varity_R		0.49
gMVP		0.48
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35033671; hg19: chr18-10759840; COSMIC: COSV57440597; COSMIC: COSV57440597;