rs9959296

chr18-10752862-G-Achr18-10752862-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378183.1(PIEZO2):c.3941C>T(p.Ser1314Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,536,490 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (52 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.11

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=0.0068618655).
• BP6: Variant 18-10752862-G-A is Benign according to our data. Variant chr18-10752862-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2037/152238) while in subpopulation AFR AF= 0.0471 (1955/41538). AF 95% confidence interval is 0.0453. There are 44 homozygotes in gnomad4. There are 964 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.3941C>T	p.Ser1314Phe	missense_variant	28/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.3941C>T	p.Ser1314Phe	missense_variant	28/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2035 AN: 152120 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00314 AC: 442 AN: 140952 Hom.: 8 AF XY: 0.00215 AC XY: 162 AN XY: 75438

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.000952

GnomAD4 exome AF: 0.00147 AC: 2041 AN: 1384252 Hom.: 52 Cov.: 32 AF XY: 0.00127 AC XY: 870 AN XY: 682918

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000632

Gnomad4 FIN exome AF: 0.0000287

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.0134 AC: 2037 AN: 152238 Hom.: 44 Cov.: 33 AF XY: 0.0130 AC XY: 964 AN XY: 74410

Gnomad4 AFR AF: 0.0471

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00224 Hom.: 12

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0542 AC: 75

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00468 AC: 98

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

Gordon syndrome;C0796033:Marden-Walker syndrome;C1862472:Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome;C4310692:Arthrogryposis, distal, with impaired proprioception and touch Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	24
Dann	Benign	0.95
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0069	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;.;N
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.92	N;.;.;.
REVEL	Benign	0.027
Sift	Benign	0.63	T;.;.;.
Sift4G	Benign	0.39	T;T;T;T
Vest4		0.52
MVP		0.043
MPC		0.34
ClinPred		0.012	T
GERP RS		4.1
Varity_R		0.055
gMVP		0.39

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: rs9959296; hg19: chr18-10752860;