18-10763009-T-C

Variant names:

• chr18-10763009-T-C
• rs7227167
• NM_001378183.1:c.3036A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):​c.3036A>G​(p.Thr1012Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,537,182 control chromosomes in the GnomAD database, including 496,371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52906 hom., cov: 35)
  • Exomes 𝑓: 0.80 (443465 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.382

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-10763009-T-C is Benign according to our data. Variant chr18-10763009-T-C is described in ClinVar as [Benign]. Clinvar id is 261504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10763009-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.382 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.3036A>G	p.Thr1012Thr	synonymous_variant	Exon 22 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.3036A>G	p.Thr1012Thr	synonymous_variant	Exon 22 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes AF: 0.830 AC: 126324 AN: 152176 Hom.: 52852 Cov.: 35

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.710

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.819

GnomAD3 exomes AF: 0.795 AC: 114981 AN: 144596 Hom.: 46039 AF XY: 0.794 AC XY: 61242 AN XY: 77164

Gnomad AFR exome AF: 0.934

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.840

Gnomad EAS exome AF: 0.914

Gnomad SAS exome AF: 0.760

Gnomad FIN exome AF: 0.775

Gnomad NFE exome AF: 0.795

Gnomad OTH exome AF: 0.806

GnomAD4 exome AF: 0.799 AC: 1107155 AN: 1384888 Hom.: 443465 Cov.: 59 AF XY: 0.798 AC XY: 545284 AN XY: 683362

Gnomad4 AFR exome AF: 0.935

Gnomad4 AMR exome AF: 0.727

Gnomad4 ASJ exome AF: 0.838

Gnomad4 EAS exome AF: 0.902

Gnomad4 SAS exome AF: 0.765

Gnomad4 FIN exome AF: 0.776

Gnomad4 NFE exome AF: 0.796

Gnomad4 OTH exome AF: 0.812

GnomAD4 genome AF: 0.830 AC: 126438 AN: 152294 Hom.: 52906 Cov.: 35 AF XY: 0.829 AC XY: 61752 AN XY: 74456

Gnomad4 AFR AF: 0.933

Gnomad4 AMR AF: 0.758

Gnomad4 ASJ AF: 0.846

Gnomad4 EAS AF: 0.913

Gnomad4 SAS AF: 0.764

Gnomad4 FIN AF: 0.789

Gnomad4 NFE AF: 0.789

Gnomad4 OTH AF: 0.822

Alfa AF: 0.787 Hom.: 8370

Bravo AF: 0.835

Asia WGS AF: 0.873 AC: 3038 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.36
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs7227167; hg19: chr18-10763007;