chr18-10691359-G-A

Position:

• chr18-10691359-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):​c.7215C>T​(p.Ala2405Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,610,936 control chromosomes in the GnomAD database, including 88,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6284 hom., cov: 31)
  • Exomes 𝑓: 0.33 (82265 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.584

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 18-10691359-G-A is Benign according to our data. Variant chr18-10691359-G-A is described in ClinVar as [Benign]. Clinvar id is 261526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10691359-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.584 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.7215C>T	p.Ala2405Ala	synonymous_variant	48/56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.7215C>T	p.Ala2405Ala	synonymous_variant	48/56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41579 AN: 151860 Hom.: 6282 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.282 AC: 70105 AN: 248420 Hom.: 10932 AF XY: 0.289 AC XY: 38811 AN XY: 134266

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.261

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.298

GnomAD4 exome AF: 0.330 AC: 480888 AN: 1458956 Hom.: 82265 Cov.: 35 AF XY: 0.329 AC XY: 238437 AN XY: 725722

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.346

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.260

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.354

Gnomad4 OTH exome AF: 0.309

GnomAD4 genome AF: 0.274 AC: 41589 AN: 151980 Hom.: 6284 Cov.: 31 AF XY: 0.270 AC XY: 20066 AN XY: 74248

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.355

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.285

Alfa AF: 0.315 Hom.: 5582

Bravo AF: 0.259

Asia WGS AF: 0.170 AC: 595 AN: 3478

EpiCase AF: 0.353

EpiControl AF: 0.343

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2019	- -

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	-0.43
CADD	Benign	4.0
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs3748421; hg19: chr18-10691357; COSMIC: COSV53286736;