rs4796901

chr18-10704621-C-Gchr18-10704621-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.6031G>C(p.Glu2011Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,536,928 control chromosomes in the GnomAD database, including 42,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3239 hom., cov: 33)
  • Exomes 𝑓: 0.24 (38930 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.53

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001565665).
• BP6: Variant 18-10704621-C-G is Benign according to our data. Variant chr18-10704621-C-G is described in ClinVar as [Benign]. Clinvar id is 261519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10704621-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.6031G>C	p.Glu2011Gln	missense_variant	42/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.6031G>C	p.Glu2011Gln	missense_variant	42/56		NM_001378183.1
	ENST00000584167.1	n.37+288C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30696 AN: 152072 Hom.: 3237 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.204

GnomAD3 exomes AF: 0.225 AC: 31886 AN: 141604 Hom.: 3670 AF XY: 0.230 AC XY: 17402 AN XY: 75742

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.186

Gnomad SAS exome AF: 0.277

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.235 AC: 325556 AN: 1384738 Hom.: 38930 Cov.: 33 AF XY: 0.236 AC XY: 161530 AN XY: 683290

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.225

GnomAD4 genome AF: 0.202 AC: 30703 AN: 152190 Hom.: 3239 Cov.: 33 AF XY: 0.202 AC XY: 15045 AN XY: 74406

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.202

Alfa AF: 0.209 Hom.: 2123

Bravo AF: 0.198

TwinsUK AF: 0.242 AC: 897

ALSPAC AF: 0.241 AC: 929

ESP6500AA AF: 0.149 AC: 206

ESP6500EA AF: 0.227 AC: 723

ExAC AF: 0.219 AC: 4437

Asia WGS AF: 0.214 AC: 743 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	Oct 02, 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
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	22
Dann	Benign	0.89
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;.;.;M
MutationTaster	Benign	0.00074	P;P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.063	T;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D
Vest4		0.24
MPC		0.92
ClinPred		0.020	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.67

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: rs4796901; hg19: chr18-10704619;