rs79992793

Variant names:

• chr18-10699089-C-G
• rs79992793
• NM_001378183.1:c.6530G>C

Your query was ambiguous. Multiple possible variants found:

• chr18-10699089-C-G
• chr18-10699089-C-T

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.6530G>C​(p.Arg2177Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00593 in 1,537,244 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (127 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.74
• Publications: 3 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=0.002460152).
• BP6: Variant 18-10699089-C-G is Benign according to our data. Variant chr18-10699089-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.6530G>C	p.Arg2177Thr	missense_variant	Exon 44 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.6530G>C	p.Arg2177Thr	missense_variant	Exon 44 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 852 AN: 152202 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0768

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00962 AC: 1362 AN: 141568 AF XY: 0.00938

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.000238

Gnomad EAS exome AF: 0.0870

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00458

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00597 AC: 8267 AN: 1384924 Hom.: 127 Cov.: 31 AF XY: 0.00583 AC XY: 3982 AN XY: 683388

African (AFR) AF: 0.000791 AC: 25 AN: 31594

American (AMR) AF: 0.00188 AC: 67 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25182

East Asian (EAS) AF: 0.0749 AC: 2678 AN: 35734

South Asian (SAS) AF: 0.00313 AC: 248 AN: 79234

European-Finnish (FIN) AF: 0.00297 AC: 104 AN: 34988

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5694

European-Non Finnish (NFE) AF: 0.00428 AC: 4615 AN: 1078884

Other (OTH) AF: 0.00901 AC: 522 AN: 57914

GnomAD4 genome AF: 0.00558 AC: 850 AN: 152320 Hom.: 14 Cov.: 32 AF XY: 0.00576 AC XY: 429 AN XY: 74476

African (AFR) AF: 0.00156 AC: 65 AN: 41576

American (AMR) AF: 0.00327 AC: 50 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0766 AC: 397 AN: 5182

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00410 AC: 279 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00625 Hom.: 13

Bravo AF: 0.00605

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00289 AC: 4

ESP6500EA AF: 0.00283 AC: 9

ExAC AF: 0.00384 AC: 82

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Benign	0.58
DEOGEN2	Benign	0.019	.;T;.;T
Eigen	Benign	0.089
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M;.;.;M
PhyloP100		5.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.19	T;.;.;.
Sift4G	Benign	0.42	T;T;T;T
Vest4		0.35
MVP		0.32
MPC		0.47
ClinPred		0.021	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.62
Mutation Taster		=80/20	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: rs79992793; hg19: chr18-10699087; COSMIC: COSV53292709;