rs16975188

chr18-10696476-G-A

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.6891C>T(p.Ser2297=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,614,084 control chromosomes in the GnomAD database, including 649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (339 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (310 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.393

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=-0.56).
• BP6: Variant 18-10696476-G-A is Benign according to our data. Variant chr18-10696476-G-A is described in ClinVar as [Benign]. Clinvar id is 261524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10696476-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.393 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.6891C>T	p.Ser2297=	synonymous_variant	46/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.6891C>T	p.Ser2297=	synonymous_variant	46/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5444 AN: 152142 Hom.: 334 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.00990 AC: 2490 AN: 251476 Hom.: 133 AF XY: 0.00726 AC XY: 986 AN XY: 135906

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00795

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00408 AC: 5965 AN: 1461824 Hom.: 310 Cov.: 34 AF XY: 0.00363 AC XY: 2639 AN XY: 727220

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.00892

Gnomad4 ASJ exome AF: 0.00784

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000356

Gnomad4 OTH exome AF: 0.00934

GnomAD4 genome AF: 0.0359 AC: 5466 AN: 152260 Hom.: 339 Cov.: 33 AF XY: 0.0348 AC XY: 2592 AN XY: 74466

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0183 Hom.: 81

Bravo AF: 0.0404

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000771

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 25, 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
BayesDel_noAF	Benign	-0.56
Cadd	Benign	1.2
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16975188; hg19: chr18-10696474;