rs5024299

Variant names:

• chr18-10741013-G-A
• rs5024299
• NM_001378183.1:c.4708+18C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001378183.1(PIEZO2):​c.4708+18C>T variant causes a intron change. The variant allele was found at a frequency of 0.802 in 1,534,072 control chromosomes in the GnomAD database, including 495,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53402 hom., cov: 32)
  • Exomes 𝑓: 0.80 (441805 hom.)
• Consequence: PIEZO2 NM_001378183.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.11
• Publications: 10 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 18-10741013-G-A is Benign according to our data. Variant chr18-10741013-G-A is described in ClinVar as Benign. ClinVar VariationId is 261510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.4708+18C>T		intron	N/A	NP_001365112.1
	PIEZO2	NM_001410871.1		c.4708+18C>T		intron	N/A	NP_001397800.1
	PIEZO2	NM_022068.4		c.4633+18C>T		intron	N/A	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.4708+18C>T		intron	N/A	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.4633+18C>T		intron	N/A	ENSP00000421377.3
	PIEZO2	ENST00000579949.2	TSL:2	c.331C>T	p.Pro111Ser	missense	Exon 4 of 4	ENSP00000477311.1

Frequencies

GnomAD3 genomes AF: 0.834 AC: 126721 AN: 152030 Hom.: 53346 Cov.: 32

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.787

Gnomad OTH AF: 0.824

GnomAD2 exomes AF: 0.794 AC: 112605 AN: 141888 AF XY: 0.791

Gnomad AFR exome AF: 0.960

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.831

Gnomad EAS exome AF: 0.907

Gnomad FIN exome AF: 0.749

Gnomad NFE exome AF: 0.794

Gnomad OTH exome AF: 0.804

GnomAD4 exome AF: 0.799 AC: 1103549 AN: 1381924 Hom.: 441805 Cov.: 36 AF XY: 0.797 AC XY: 543508 AN XY: 682120

African (AFR) AF: 0.963 AC: 30384 AN: 31552

American (AMR) AF: 0.727 AC: 25942 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 20847 AN: 25154

East Asian (EAS) AF: 0.898 AC: 32091 AN: 35724

South Asian (SAS) AF: 0.762 AC: 60299 AN: 79164

European-Finnish (FIN) AF: 0.753 AC: 26343 AN: 34992

Middle Eastern (MID) AF: 0.836 AC: 4756 AN: 5688

European-Non Finnish (NFE) AF: 0.795 AC: 855853 AN: 1076138

Other (OTH) AF: 0.813 AC: 47034 AN: 57818

GnomAD4 genome AF: 0.834 AC: 126838 AN: 152148 Hom.: 53402 Cov.: 32 AF XY: 0.832 AC XY: 61855 AN XY: 74372

African (AFR) AF: 0.956 AC: 39706 AN: 41542

American (AMR) AF: 0.759 AC: 11596 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2909 AN: 3472

East Asian (EAS) AF: 0.909 AC: 4701 AN: 5170

South Asian (SAS) AF: 0.764 AC: 3672 AN: 4808

European-Finnish (FIN) AF: 0.765 AC: 8095 AN: 10584

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.787 AC: 53508 AN: 67972

Other (OTH) AF: 0.827 AC: 1748 AN: 2114

Alfa AF: 0.815 Hom.: 12957

Bravo AF: 0.841

Asia WGS AF: 0.871 AC: 3029 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	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
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.83
PhyloP100		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs5024299; hg19: chr18-10741011; COSMIC: COSV57436818;