rs79992793

chr18-10699089-C-Gchr18-10699089-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378183.1(PIEZO2):c.6530G>C(p.Arg2177Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00593 in 1,537,244 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (127 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.74

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002460152).
• BP6: Variant 18-10699089-C-G is Benign according to our data. Variant chr18-10699089-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 261522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10699089-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.6530G>C	p.Arg2177Thr	missense_variant	44/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.6530G>C	p.Arg2177Thr	missense_variant	44/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 852 AN: 152202 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0768

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00962 AC: 1362 AN: 141568 Hom.: 60 AF XY: 0.00938 AC XY: 710 AN XY: 75708

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.000238

Gnomad EAS exome AF: 0.0870

Gnomad SAS exome AF: 0.00299

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00458

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00597 AC: 8267 AN: 1384924 Hom.: 127 Cov.: 31 AF XY: 0.00583 AC XY: 3982 AN XY: 683388

Gnomad4 AFR exome AF: 0.000791

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.0749

Gnomad4 SAS exome AF: 0.00313

Gnomad4 FIN exome AF: 0.00297

Gnomad4 NFE exome AF: 0.00428

Gnomad4 OTH exome AF: 0.00901

GnomAD4 genome AF: 0.00558 AC: 850 AN: 152320 Hom.: 14 Cov.: 32 AF XY: 0.00576 AC XY: 429 AN XY: 74476

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0766

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00625 Hom.: 13

Bravo AF: 0.00605

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00289 AC: 4

ESP6500EA AF: 0.00283 AC: 9

ExAC AF: 0.00384 AC: 82

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 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
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	22
Dann	Benign	0.58
Eigen	Benign	0.089
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M;.;.;M
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.19	T;.;.;.
Sift4G	Benign	0.42	T;T;T;T
Vest4		0.35
MVP		0.32
MPC		0.47
ClinPred		0.021	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.62

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: rs79992793; hg19: chr18-10699087; COSMIC: COSV53292709;