rs16975188

Variant names:

• chr18-10696476-G-A
• rs16975188
• NM_001378183.1:c.6891C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-10696476-G-A
• chr18-10696476-G-C

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.6891C>T​(p.Ser2297Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,614,084 control chromosomes in the GnomAD database, including 649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (339 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (310 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.393
• Publications: 2 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=-0.56).
• BP6: Variant 18-10696476-G-A is Benign according to our data. Variant chr18-10696476-G-A is described in ClinVar as Benign. ClinVar VariationId is 261524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.393 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 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.6891C>T	p.Ser2297Ser	synonymous	Exon 46 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.6627C>T	p.Ser2209Ser	synonymous	Exon 44 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.6552C>T	p.Ser2184Ser	synonymous	Exon 42 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.6891C>T	p.Ser2297Ser	synonymous	Exon 46 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.6552C>T	p.Ser2184Ser	synonymous	Exon 42 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.6627C>T	p.Ser2209Ser	synonymous	Exon 44 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5444 AN: 152142 Hom.: 334 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.00990 AC: 2490 AN: 251476 AF XY: 0.00726

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00795

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00408 AC: 5965 AN: 1461824 Hom.: 310 Cov.: 34 AF XY: 0.00363 AC XY: 2639 AN XY: 727220

African (AFR) AF: 0.129 AC: 4328 AN: 33474

American (AMR) AF: 0.00892 AC: 399 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00784 AC: 205 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00784 AC: 45 AN: 5738

European-Non Finnish (NFE) AF: 0.000356 AC: 396 AN: 1112000

Other (OTH) AF: 0.00934 AC: 564 AN: 60382

GnomAD4 genome AF: 0.0359 AC: 5466 AN: 152260 Hom.: 339 Cov.: 33 AF XY: 0.0348 AC XY: 2592 AN XY: 74466

African (AFR) AF: 0.121 AC: 5022 AN: 41522

American (AMR) AF: 0.0198 AC: 303 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68022

Other (OTH) AF: 0.0274 AC: 58 AN: 2116

Alfa AF: 0.0184 Hom.: 111

Bravo AF: 0.0404

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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	-0.56
CADD	Benign	1.2
DANN	Benign	0.76
PhyloP100		0.39
Mutation Taster		=95/5	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: rs16975188; hg19: chr18-10696474;