rs7234309

Variant names:

• chr18-10752668-C-T
• rs7234309
• NM_001378183.1:c.4135G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378183.1(PIEZO2):​c.4135G>A​(p.Val1379Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,536,748 control chromosomes in the GnomAD database, including 60,652 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7345 hom., cov: 33)
  • Exomes 𝑓: 0.27 (53307 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.84
• Publications: 21 publications found

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]

PIEZO2 Gene-Disease associations (from GenCC):

• Gordon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• arthrogryposis, distal, with impaired proprioception and touch

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• connective tissue disorder

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Marden-Walker syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2963705E-4).
• BP6: Variant 18-10752668-C-T is Benign according to our data. Variant chr18-10752668-C-T is described in ClinVar as Benign. ClinVar VariationId is 261508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378183.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.4135G>A	p.Val1379Ile	missense	Exon 28 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.4135G>A	p.Val1379Ile	missense	Exon 28 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.4060G>A	p.Val1354Ile	missense	Exon 26 of 52	NP_071351.2	Q9H5I5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.4135G>A	p.Val1379Ile	missense	Exon 28 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.4060G>A	p.Val1354Ile	missense	Exon 26 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.4135G>A	p.Val1379Ile	missense	Exon 28 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46037 AN: 151934 Hom.: 7327 Cov.: 33

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.303

GnomAD2 exomes AF: 0.272 AC: 38581 AN: 141626 AF XY: 0.271

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.274 AC: 378916 AN: 1384696 Hom.: 53307 Cov.: 34 AF XY: 0.271 AC XY: 185349 AN XY: 683280

African (AFR) AF: 0.395 AC: 12470 AN: 31584

American (AMR) AF: 0.192 AC: 6843 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 6922 AN: 25182

East Asian (EAS) AF: 0.437 AC: 15622 AN: 35734

South Asian (SAS) AF: 0.228 AC: 18042 AN: 79226

European-Finnish (FIN) AF: 0.225 AC: 7856 AN: 34984

Middle Eastern (MID) AF: 0.318 AC: 1810 AN: 5696

European-Non Finnish (NFE) AF: 0.271 AC: 292507 AN: 1078694

Other (OTH) AF: 0.291 AC: 16844 AN: 57900

GnomAD4 genome AF: 0.303 AC: 46077 AN: 152052 Hom.: 7345 Cov.: 33 AF XY: 0.301 AC XY: 22391 AN XY: 74314

African (AFR) AF: 0.390 AC: 16149 AN: 41454

American (AMR) AF: 0.241 AC: 3680 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 936 AN: 3472

East Asian (EAS) AF: 0.473 AC: 2443 AN: 5168

South Asian (SAS) AF: 0.246 AC: 1187 AN: 4818

European-Finnish (FIN) AF: 0.208 AC: 2203 AN: 10566

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18384 AN: 67970

Other (OTH) AF: 0.311 AC: 657 AN: 2112

Alfa AF: 0.289 Hom.: 12984

Bravo AF: 0.315

TwinsUK AF: 0.281 AC: 1043

ALSPAC AF: 0.265 AC: 1021

ESP6500AA AF: 0.397 AC: 549

ESP6500EA AF: 0.271 AC: 863

ExAC AF: 0.245 AC: 4919

Asia WGS AF: 0.385 AC: 1338 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome (1)
-	-	1	Arthrogryposis, distal, with impaired proprioception and touch (1)
-	-	1	Gordon syndrome (1)
-	-	1	Marden-Walker syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.025	T
Eigen	Benign	0.097
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.00083	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.056
Sift	Benign	0.24	T
Sift4G	Benign	0.14	T
Vest4		0.17
MPC		0.25
ClinPred		0.0068	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.54
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7234309; hg19: chr18-10752666; COSMIC: COSV57439950; COSMIC: COSV57439950;