rs113682091

Positions:

• chr18-10699131-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378183.1(PIEZO2):​c.6488C>A​(p.Ala2163Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0798 in 1,537,064 control chromosomes in the GnomAD database, including 6,147 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1370 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4777 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.37

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018732846).
• BP6: Variant 18-10699131-G-T is Benign according to our data. Variant chr18-10699131-G-T is described in ClinVar as [Benign]. Clinvar id is 261521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10699131-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.6488C>A	p.Ala2163Asp	missense_variant	44/56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.6488C>A	p.Ala2163Asp	missense_variant	44/56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16655 AN: 152036 Hom.: 1356 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.0611

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.0915

GnomAD3 exomes AF: 0.0697 AC: 9874 AN: 141580 Hom.: 525 AF XY: 0.0683 AC XY: 5172 AN XY: 75710

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.0508

Gnomad ASJ exome AF: 0.0645

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.0695

Gnomad FIN exome AF: 0.0554

Gnomad NFE exome AF: 0.0708

Gnomad OTH exome AF: 0.0612

GnomAD4 exome AF: 0.0766 AC: 106025 AN: 1384910 Hom.: 4777 Cov.: 32 AF XY: 0.0757 AC XY: 51723 AN XY: 683384

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.0562

Gnomad4 ASJ exome AF: 0.0641

Gnomad4 EAS exome AF: 0.000784

Gnomad4 SAS exome AF: 0.0681

Gnomad4 FIN exome AF: 0.0561

Gnomad4 NFE exome AF: 0.0768

Gnomad4 OTH exome AF: 0.0760

GnomAD4 genome AF: 0.110 AC: 16686 AN: 152154 Hom.: 1370 Cov.: 32 AF XY: 0.107 AC XY: 7935 AN XY: 74372

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.0674

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.0612

Gnomad4 FIN AF: 0.0611

Gnomad4 NFE AF: 0.0694

Gnomad4 OTH AF: 0.0896

Alfa AF: 0.0692 Hom.: 540

Bravo AF: 0.117

TwinsUK AF: 0.0825 AC: 306

ALSPAC AF: 0.0812 AC: 313

ExAC AF: 0.0751 AC: 1612

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.7
DANN	Benign	0.69
DEOGEN2	Benign	0.0043	.;T;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.27	T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N;.;.;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.9	N;.;.;.
REVEL	Benign	0.13
Sift	Benign	0.78	T;.;.;.
Sift4G	Benign	0.68	T;T;T;T
Vest4		0.085
MPC		0.45
ClinPred		0.0029	T
GERP RS		5.8
Varity_R		0.036
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs113682091; hg19: chr18-10699129; COSMIC: COSV53290641;