18-10699019-G-A

Variant names:

• chr18-10699019-G-A
• rs73945841
• NM_001378183.1:c.6600C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):​c.6600C>T​(p.Phe2200Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,537,110 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (96 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.34
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 18-10699019-G-A is Benign according to our data. Variant chr18-10699019-G-A is described in ClinVar as Benign. ClinVar VariationId is 261523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.067 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.6600C>T	p.Phe2200Phe	synonymous	Exon 44 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.6336C>T	p.Phe2112Phe	synonymous	Exon 42 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.6261C>T	p.Phe2087Phe	synonymous	Exon 40 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.6600C>T	p.Phe2200Phe	synonymous	Exon 44 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.6261C>T	p.Phe2087Phe	synonymous	Exon 40 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.6336C>T	p.Phe2112Phe	synonymous	Exon 42 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3126 AN: 152194 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0692

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00994

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00560 AC: 793 AN: 141610 AF XY: 0.00465

Gnomad AFR exome AF: 0.0723

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.00546

GnomAD4 exome AF: 0.00247 AC: 3416 AN: 1384798 Hom.: 96 Cov.: 31 AF XY: 0.00226 AC XY: 1545 AN XY: 683346

African (AFR) AF: 0.0749 AC: 2365 AN: 31594

American (AMR) AF: 0.00538 AC: 192 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00798 AC: 201 AN: 25182

East Asian (EAS) AF: 0.0000840 AC: 3 AN: 35734

South Asian (SAS) AF: 0.000189 AC: 15 AN: 79236

European-Finnish (FIN) AF: 0.0000287 AC: 1 AN: 34858

Middle Eastern (MID) AF: 0.00580 AC: 33 AN: 5694

European-Non Finnish (NFE) AF: 0.000254 AC: 274 AN: 1078886

Other (OTH) AF: 0.00573 AC: 332 AN: 57914

GnomAD4 genome AF: 0.0206 AC: 3133 AN: 152312 Hom.: 96 Cov.: 32 AF XY: 0.0195 AC XY: 1455 AN XY: 74474

African (AFR) AF: 0.0691 AC: 2872 AN: 41568

American (AMR) AF: 0.00993 AC: 152 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68024

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0227 Hom.: 62

Bravo AF: 0.0226

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.4
DANN	Benign	0.71
PhyloP100		2.3
Mutation Taster		=297/3	polymorphism

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: rs73945841; hg19: chr18-10699017;