rs3748428

chr18-10681714-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.7726G>A(p.Val2576Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,609,028 control chromosomes in the GnomAD database, including 15,512 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 (1059 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14453 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.214

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=0.0011119545).
• BP6: Variant 18-10681714-C-T is Benign according to our data. Variant chr18-10681714-C-T is described in ClinVar as [Benign]. Clinvar id is 261530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10681714-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.7726G>A	p.Val2576Ile	missense_variant	51/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.7726G>A	p.Val2576Ile	missense_variant	51/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16161 AN: 151964 Hom.: 1058 Cov.: 31

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.131 AC: 32800 AN: 250944 Hom.: 2338 AF XY: 0.133 AC XY: 18081 AN XY: 135614

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.137 AC: 199401 AN: 1456946 Hom.: 14453 Cov.: 31 AF XY: 0.137 AC XY: 99392 AN XY: 725048

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.235

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.106 AC: 16157 AN: 152082 Hom.: 1059 Cov.: 31 AF XY: 0.108 AC XY: 8043 AN XY: 74328

Gnomad4 AFR AF: 0.0322

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.114

Alfa AF: 0.133 Hom.: 3580

Bravo AF: 0.103

TwinsUK AF: 0.143 AC: 531

ALSPAC AF: 0.138 AC: 530

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.131 AC: 1124

ExAC AF: 0.130 AC: 15796

Asia WGS AF: 0.129 AC: 451 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.91	N;.;.;.
REVEL	Benign	0.083
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.052	T;T;T;T
Vest4		0.16
MPC		0.27
ClinPred		0.040	T
GERP RS		5.1
Varity_R		0.10
gMVP		0.31

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: rs3748428; hg19: chr18-10681711; COSMIC: COSV53289666; COSMIC: COSV53289666;