rs76488076

chr18-10787128-A-G

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.2226T>C(p.Ile742=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,535,012 control chromosomes in the GnomAD database, including 3,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (286 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3193 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00600

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=-0.59).
• BP6: Variant 18-10787128-A-G is Benign according to our data. Variant chr18-10787128-A-G is described in ClinVar as [Benign]. Clinvar id is 261502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10787128-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.006 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.2226T>C	p.Ile742=	synonymous_variant	16/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.2226T>C	p.Ile742=	synonymous_variant	16/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8391 AN: 152136 Hom.: 286 Cov.: 33

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0429

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.00461

Gnomad SAS AF: 0.0395

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0658

Gnomad OTH AF: 0.0595

GnomAD3 exomes AF: 0.0499 AC: 7159 AN: 143490 Hom.: 219 AF XY: 0.0502 AC XY: 3840 AN XY: 76534

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.0370

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.00217

Gnomad SAS exome AF: 0.0422

Gnomad FIN exome AF: 0.0853

Gnomad NFE exome AF: 0.0633

Gnomad OTH exome AF: 0.0554

GnomAD4 exome AF: 0.0653 AC: 90341 AN: 1382758 Hom.: 3193 Cov.: 35 AF XY: 0.0646 AC XY: 44082 AN XY: 682276

Gnomad4 AFR exome AF: 0.0432

Gnomad4 AMR exome AF: 0.0412

Gnomad4 ASJ exome AF: 0.0506

Gnomad4 EAS exome AF: 0.00109

Gnomad4 SAS exome AF: 0.0427

Gnomad4 FIN exome AF: 0.0842

Gnomad4 NFE exome AF: 0.0708

Gnomad4 OTH exome AF: 0.0591

GnomAD4 genome AF: 0.0551 AC: 8395 AN: 152254 Hom.: 286 Cov.: 33 AF XY: 0.0554 AC XY: 4121 AN XY: 74422

Gnomad4 AFR AF: 0.0435

Gnomad4 AMR AF: 0.0428

Gnomad4 ASJ AF: 0.0527

Gnomad4 EAS AF: 0.00462

Gnomad4 SAS AF: 0.0391

Gnomad4 FIN AF: 0.0869

Gnomad4 NFE AF: 0.0659

Gnomad4 OTH AF: 0.0594

Alfa AF: 0.0553 Hom.: 52

Bravo AF: 0.0523

Asia WGS AF: 0.0240 AC: 83 AN: 3476

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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

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	-0.59
Cadd	Benign	7.0
Dann	Benign	0.77

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: rs76488076; hg19: chr18-10787126;