chr18-10731430-C-T

Variant names:

• chr18-10731430-C-T
• rs2865121
• NM_001378183.1:c.5006G>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.5006G>A​(p.Arg1669Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,532,860 control chromosomes in the GnomAD database, including 50,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3597 hom., cov: 30)
  • Exomes 𝑓: 0.26 (47399 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.149
• Publications: 13 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• arthrogryposis, distal, with impaired proprioception and touch

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

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

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

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004354328).
• BP6: Variant 18-10731430-C-T is Benign according to our data. Variant chr18-10731430-C-T is described in ClinVar as Benign. ClinVar VariationId is 261511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 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.5006G>A	p.Arg1669Gln	missense	Exon 36 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.4907G>A	p.Arg1636Gln	missense	Exon 35 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.4832G>A	p.Arg1611Gln	missense	Exon 33 of 52	NP_071351.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.5006G>A	p.Arg1669Gln	missense	Exon 36 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.4832G>A	p.Arg1611Gln	missense	Exon 33 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.4907G>A	p.Arg1636Gln	missense	Exon 35 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30966 AN: 151460 Hom.: 3595 Cov.: 30

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.220 AC: 30682 AN: 139548 AF XY: 0.226

Gnomad AFR exome AF: 0.0785

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.257 AC: 355080 AN: 1381282 Hom.: 47399 Cov.: 32 AF XY: 0.257 AC XY: 175221 AN XY: 681710

African (AFR) AF: 0.0773 AC: 2427 AN: 31400

American (AMR) AF: 0.159 AC: 5603 AN: 35288

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6065 AN: 25108

East Asian (EAS) AF: 0.135 AC: 4788 AN: 35516

South Asian (SAS) AF: 0.225 AC: 17751 AN: 78922

European-Finnish (FIN) AF: 0.254 AC: 8874 AN: 34920

Middle Eastern (MID) AF: 0.259 AC: 1475 AN: 5686

European-Non Finnish (NFE) AF: 0.273 AC: 294186 AN: 1076720

Other (OTH) AF: 0.241 AC: 13911 AN: 57722

GnomAD4 genome AF: 0.204 AC: 30959 AN: 151578 Hom.: 3597 Cov.: 30 AF XY: 0.203 AC XY: 15047 AN XY: 74062

African (AFR) AF: 0.0862 AC: 3568 AN: 41404

American (AMR) AF: 0.193 AC: 2931 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 884 AN: 3466

East Asian (EAS) AF: 0.125 AC: 640 AN: 5136

South Asian (SAS) AF: 0.210 AC: 1012 AN: 4808

European-Finnish (FIN) AF: 0.262 AC: 2725 AN: 10404

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.273 AC: 18500 AN: 67842

Other (OTH) AF: 0.202 AC: 424 AN: 2102

Alfa AF: 0.241 Hom.: 10303

Bravo AF: 0.193

TwinsUK AF: 0.258 AC: 957

ALSPAC AF: 0.274 AC: 1057

ESP6500AA AF: 0.103 AC: 143

ESP6500EA AF: 0.279 AC: 889

ExAC AF: 0.203 AC: 4574

Asia WGS AF: 0.155 AC: 540 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.72
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.15
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.042
Sift	Benign	0.35	T
Sift4G	Benign	0.55	T
Vest4		0.099
MPC		0.35
ClinPred		0.00049	T
GERP RS		2.6
Varity_R		0.014
gMVP		0.23
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2865121; hg19: chr18-10731428; COSMIC: COSV57440592; COSMIC: COSV57440592;