rs7234309

chr18-10752668-C-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.4135G>A(p.Val1379Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,536,748 control chromosomes in the GnomAD database, including 60,652 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7345 hom., cov: 33)
  • Exomes 𝑓: 0.27 (53307 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2963705E-4).
• BP6: Variant 18-10752668-C-T is Benign according to our data. Variant chr18-10752668-C-T is described in ClinVar as [Benign]. Clinvar id is 261508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10752668-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.4135G>A	p.Val1379Ile	missense_variant	28/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.4135G>A	p.Val1379Ile	missense_variant	28/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46037 AN: 151934 Hom.: 7327 Cov.: 33

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.303

GnomAD3 exomes AF: 0.272 AC: 38581 AN: 141626 Hom.: 5827 AF XY: 0.271 AC XY: 20494 AN XY: 75732

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.223

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.274 AC: 378916 AN: 1384696 Hom.: 53307 Cov.: 34 AF XY: 0.271 AC XY: 185349 AN XY: 683280

Gnomad4 AFR exome AF: 0.395

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.275

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.303 AC: 46077 AN: 152052 Hom.: 7345 Cov.: 33 AF XY: 0.301 AC XY: 22391 AN XY: 74314

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.311

Alfa AF: 0.284 Hom.: 8014

Bravo AF: 0.315

TwinsUK AF: 0.281 AC: 1043

ALSPAC AF: 0.265 AC: 1021

ESP6500AA AF: 0.397 AC: 549

ESP6500EA AF: 0.271 AC: 863

ExAC AF: 0.245 AC: 4919

Asia WGS AF: 0.385 AC: 1338 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Gordon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Marden-Walker syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Benign	0.097
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.00083	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;.;.;L
MutationTaster	Benign	0.043	P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.53	N;.;.;.
REVEL	Benign	0.056
Sift	Benign	0.24	T;.;.;.
Sift4G	Benign	0.14	T;T;T;T
Vest4		0.17
MPC		0.25
ClinPred		0.0068	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.54

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: rs7234309; hg19: chr18-10752666; COSMIC: COSV57439950; COSMIC: COSV57439950;