rs3748428

Variant names:

• chr18-10681714-C-T
• rs3748428
• NM_001378183.1:c.7726G>A

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.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. 16/20 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:4
• Conservation: PhyloP100: 0.214
• Publications: 24 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.7726G>A	p.Val2576Ile	missense_variant	Exon 51 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.7726G>A	p.Val2576Ile	missense_variant	Exon 51 of 56		NM_001378183.1	ENSP00000501957.1

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

GnomAD2 exomes AF: 0.131 AC: 32800 AN: 250944 AF XY: 0.133

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 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

African (AFR) AF: 0.0257 AC: 859 AN: 33440

American (AMR) AF: 0.126 AC: 5602 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3607 AN: 26090

East Asian (EAS) AF: 0.235 AC: 9320 AN: 39638

South Asian (SAS) AF: 0.128 AC: 11016 AN: 86004

European-Finnish (FIN) AF: 0.131 AC: 7014 AN: 53388

Middle Eastern (MID) AF: 0.128 AC: 739 AN: 5760

European-Non Finnish (NFE) AF: 0.139 AC: 153497 AN: 1107750

Other (OTH) AF: 0.129 AC: 7747 AN: 60242

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

African (AFR) AF: 0.0322 AC: 1339 AN: 41530

American (AMR) AF: 0.127 AC: 1932 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 503 AN: 3472

East Asian (EAS) AF: 0.185 AC: 957 AN: 5174

South Asian (SAS) AF: 0.128 AC: 617 AN: 4804

European-Finnish (FIN) AF: 0.130 AC: 1368 AN: 10552

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9139 AN: 67966

Other (OTH) AF: 0.114 AC: 241 AN: 2106

Alfa AF: 0.129 Hom.: 4666

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

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
DEOGEN2	Benign	0.41	.;T;.;T
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
MutationAssessor	Benign	1.4	.;.;.;L
PhyloP100		0.21
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
Mutation Taster		=100/0	polymorphism (auto)

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