chr18-10787049-G-A

Variant names:

• chr18-10787049-G-A
• rs6505592
• NM_001378183.1:c.2305C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):​c.2305C>T​(p.Leu769Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 1,529,326 control chromosomes in the GnomAD database, including 570,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (54824 hom., cov: 31)
  • Exomes 𝑓: 0.86 (515351 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.59
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 18-10787049-G-A is Benign according to our data. Variant chr18-10787049-G-A is described in ClinVar as Benign. ClinVar VariationId is 261503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 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.2305C>T	p.Leu769Leu	synonymous	Exon 16 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.2305C>T	p.Leu769Leu	synonymous	Exon 16 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.2305C>T	p.Leu769Leu	synonymous	Exon 16 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.2305C>T	p.Leu769Leu	synonymous	Exon 16 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.2305C>T	p.Leu769Leu	synonymous	Exon 16 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.2305C>T	p.Leu769Leu	synonymous	Exon 16 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.848 AC: 128972 AN: 152014 Hom.: 54779 Cov.: 31

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.874

Gnomad ASJ AF: 0.842

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.844

GnomAD2 exomes AF: 0.860 AC: 121355 AN: 141046 AF XY: 0.861

Gnomad AFR exome AF: 0.792

Gnomad AMR exome AF: 0.859

Gnomad ASJ exome AF: 0.831

Gnomad EAS exome AF: 0.932

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.865

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.865 AC: 1190866 AN: 1377194 Hom.: 515351 Cov.: 41 AF XY: 0.864 AC XY: 587476 AN XY: 679578

African (AFR) AF: 0.801 AC: 24969 AN: 31172

American (AMR) AF: 0.863 AC: 29533 AN: 34204

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 20816 AN: 25034

East Asian (EAS) AF: 0.933 AC: 33272 AN: 35646

South Asian (SAS) AF: 0.856 AC: 66597 AN: 77832

European-Finnish (FIN) AF: 0.855 AC: 30006 AN: 35086

Middle Eastern (MID) AF: 0.844 AC: 4749 AN: 5624

European-Non Finnish (NFE) AF: 0.866 AC: 931331 AN: 1074890

Other (OTH) AF: 0.859 AC: 49593 AN: 57706

GnomAD4 genome AF: 0.848 AC: 129075 AN: 152132 Hom.: 54824 Cov.: 31 AF XY: 0.850 AC XY: 63241 AN XY: 74374

African (AFR) AF: 0.805 AC: 33364 AN: 41468

American (AMR) AF: 0.874 AC: 13358 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.842 AC: 2925 AN: 3472

East Asian (EAS) AF: 0.933 AC: 4823 AN: 5170

South Asian (SAS) AF: 0.857 AC: 4132 AN: 4824

European-Finnish (FIN) AF: 0.851 AC: 9012 AN: 10588

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.863 AC: 58667 AN: 68008

Other (OTH) AF: 0.845 AC: 1787 AN: 2114

Alfa AF: 0.846 Hom.: 17529

Bravo AF: 0.847

Asia WGS AF: 0.896 AC: 3109 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gordon syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Marden-Walker syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arthrogryposis, distal, with impaired proprioception and touch Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.29
DANN	Benign	0.43
PhyloP100		-1.6
Mutation Taster		=98/2	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: rs6505592; hg19: chr18-10787047; COSMIC: COSV108125173;