rs7241380

chr18-10762964-G-Achr18-10762964-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):c.3081C>T(p.Leu1027=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,536,988 control chromosomes in the GnomAD database, including 481,780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46624 hom., cov: 35)
  • Exomes 𝑓: 0.79 (435156 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.286

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 18-10762964-G-A is Benign according to our data. Variant chr18-10762964-G-A is described in ClinVar as [Benign]. Clinvar id is 261505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10762964-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.286 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.3081C>T	p.Leu1027=	synonymous_variant	22/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.3081C>T	p.Leu1027=	synonymous_variant	22/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118939 AN: 152098 Hom.: 46596 Cov.: 35

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.710

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.782

GnomAD3 exomes AF: 0.775 AC: 111788 AN: 144308 Hom.: 43602 AF XY: 0.777 AC XY: 59907 AN XY: 77052

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.840

Gnomad EAS exome AF: 0.881

Gnomad SAS exome AF: 0.757

Gnomad FIN exome AF: 0.775

Gnomad NFE exome AF: 0.794

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.792 AC: 1096951 AN: 1384772 Hom.: 435156 Cov.: 60 AF XY: 0.791 AC XY: 540664 AN XY: 683318

Gnomad4 AFR exome AF: 0.776

Gnomad4 AMR exome AF: 0.680

Gnomad4 ASJ exome AF: 0.838

Gnomad4 EAS exome AF: 0.880

Gnomad4 SAS exome AF: 0.761

Gnomad4 FIN exome AF: 0.775

Gnomad4 NFE exome AF: 0.795

Gnomad4 OTH exome AF: 0.799

GnomAD4 genome AF: 0.782 AC: 119013 AN: 152216 Hom.: 46624 Cov.: 35 AF XY: 0.782 AC XY: 58207 AN XY: 74422

Gnomad4 AFR AF: 0.776

Gnomad4 AMR AF: 0.728

Gnomad4 ASJ AF: 0.846

Gnomad4 EAS AF: 0.881

Gnomad4 SAS AF: 0.760

Gnomad4 FIN AF: 0.788

Gnomad4 NFE AF: 0.788

Gnomad4 OTH AF: 0.785

Alfa AF: 0.780 Hom.: 10315

Bravo AF: 0.780

Asia WGS AF: 0.846 AC: 2942 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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

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
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.6
Dann	Benign	0.71

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: rs7241380; hg19: chr18-10762962;