rs147666072

chr18-10677859-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001378183.1(PIEZO2):c.7969G>A(p.Ala2657Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,590,704 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 6.37

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038327932).
• BP6: Variant 18-10677859-C-T is Benign according to our data. Variant chr18-10677859-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445793.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.7969G>A	p.Ala2657Thr	missense_variant	53/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.7969G>A	p.Ala2657Thr	missense_variant	53/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 165 AN: 147766 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000902

Gnomad ASJ AF: 0.00585

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000503

GnomAD3 exomes AF: 0.00106 AC: 239 AN: 226266 Hom.: 0 AF XY: 0.00114 AC XY: 140 AN XY: 122642

Gnomad AFR exome AF: 0.000512

Gnomad AMR exome AF: 0.000540

Gnomad ASJ exome AF: 0.00609

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000122

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00129 AC: 1868 AN: 1442820 Hom.: 6 Cov.: 30 AF XY: 0.00129 AC XY: 924 AN XY: 717126

Gnomad4 AFR exome AF: 0.000218

Gnomad4 AMR exome AF: 0.000655

Gnomad4 ASJ exome AF: 0.00479

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000270

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.00146

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00112 AC: 165 AN: 147884 Hom.: 1 Cov.: 32 AF XY: 0.00100 AC XY: 72 AN XY: 71898

Gnomad4 AFR AF: 0.000397

Gnomad4 AMR AF: 0.000901

Gnomad4 ASJ AF: 0.00585

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000224

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.000498

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00138

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000840 AC: 102

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00219

EpiControl AF: 0.00192

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.7630G>A (p.A2544T) alteration is located in exon 49 (coding exon 49) of the PIEZO2 gene. This alteration results from a G to A substitution at nucleotide position 7630, causing the alanine (A) at amino acid position 2544 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 01, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6. -

PIEZO2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.038	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
REVEL	Uncertain	0.40
Sift4G	Uncertain	0.031	D;D;D;D
Vest4		0.74
MVP		0.043
MPC		0.89
ClinPred		0.035	T
GERP RS		5.6
Varity_R		0.27
gMVP		0.38

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: rs147666072; hg19: chr18-10677856;