18-10705737-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001378183.1(PIEZO2):c.5598G>A(p.Thr1866Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,525,144 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1866T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 56 hom., cov: 32)

Exomes 𝑓: 0.029 ( 670 hom. )

Consequence

PIEZO2
NM_001378183.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.40

Publications

3 publications found

Variant links:

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

PIEZO2 links:

ENSG00000264843 (HGNC:):

ENSG00000264843 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 18-10705737-C-T is Benign according to our data. Variant chr18-10705737-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.4 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0224 (3404/152230) while in subpopulation NFE AF = 0.034 (2314/68002). AF 95% confidence interval is 0.0329. There are 56 homozygotes in GnomAd4. There are 1619 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 56 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1 link	c.5598G>A	p.Thr1866Thr	synonymous_variant	Exon 41 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1 link	c.5598G>A	p.Thr1866Thr	synonymous_variant	Exon 41 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3404

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00539

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0287

Gnomad ASJ

AF:

0.0608

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00788

Gnomad FIN

AF:

0.00574

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.0340

Gnomad OTH

AF:

0.0368

GnomAD2 exomes

AF:

0.0250

AC:

3242

AN:

129582

AF XY:

0.0249

show subpopulations

Gnomad AFR exome

AF:

0.00492

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.0591

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00863

Gnomad NFE exome

AF:

0.0369

Gnomad OTH exome

AF:

0.0377

GnomAD4 exome

AF:

0.0290

AC:

39762

AN:

1372914

Hom.:

670

Cov.:

AF XY:

0.0287

AC XY:

19402

AN XY:

675994

show subpopulations

African (AFR)

AF:

0.00474

AC:

148

AN:

31214

American (AMR)

AF:

0.0206

AC:

714

AN:

34686

Ashkenazi Jewish (ASJ)

AF:

0.0595

AC:

1454

AN:

24418

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35590

South Asian (SAS)

AF:

0.0105

AC:

823

AN:

78414

European-Finnish (FIN)

AF:

0.00712

AC:

243

AN:

34138

Middle Eastern (MID)

AF:

0.0453

AC:

254

AN:

5608

European-Non Finnish (NFE)

AF:

0.0322

AC:

34512

AN:

1071548

Other (OTH)

AF:

0.0282

AC:

1613

AN:

57298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

2217

4433

6650

8866

11083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1292

2584

3876

5168

6460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0224

AC:

3404

AN:

152230

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

1619

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00537

AC:

223

AN:

41530

American (AMR)

AF:

0.0287

AC:

439

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0608

AC:

211

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00788

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00574

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0514

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0340

AC:

2314

AN:

68002

Other (OTH)

AF:

0.0365

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

175

349

524

698

873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0299

Hom.:

130

Bravo

AF:

0.0239

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Jan 28, 2021

GeneDx

Significance:Likely 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.6

(source)

DANN

Benign

0.87

PhyloP100

-3.4

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over