chr18-10748605-A-T

Position:

• chr18-10748605-A-T

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.4290T>A​(p.Leu1430=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,524,030 control chromosomes in the GnomAD database, including 242,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32696 hom., cov: 32)
  • Exomes 𝑓: 0.55 (209711 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.27

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=-0.85).
• BP6: Variant 18-10748605-A-T is Benign according to our data. Variant chr18-10748605-A-T is described in ClinVar as [Benign]. Clinvar id is 261509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10748605-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.4290T>A	p.Leu1430=	synonymous_variant	30/56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.4290T>A	p.Leu1430=	synonymous_variant	30/56		NM_001378183.1	ENSP00000501957

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96295 AN: 151974 Hom.: 32645 Cov.: 32

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.603

GnomAD3 exomes AF: 0.548 AC: 71089 AN: 129772 Hom.: 20354 AF XY: 0.544 AC XY: 37629 AN XY: 69170

Gnomad AFR exome AF: 0.902

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.706

Gnomad SAS exome AF: 0.475

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.555

Gnomad OTH exome AF: 0.548

GnomAD4 exome AF: 0.548 AC: 751889 AN: 1371940 Hom.: 209711 Cov.: 37 AF XY: 0.544 AC XY: 368256 AN XY: 676414

Gnomad4 AFR exome AF: 0.906

Gnomad4 AMR exome AF: 0.418

Gnomad4 ASJ exome AF: 0.551

Gnomad4 EAS exome AF: 0.662

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.493

Gnomad4 NFE exome AF: 0.544

Gnomad4 OTH exome AF: 0.570

GnomAD4 genome AF: 0.634 AC: 96391 AN: 152090 Hom.: 32696 Cov.: 32 AF XY: 0.628 AC XY: 46688 AN XY: 74332

Gnomad4 AFR AF: 0.891

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.695

Gnomad4 SAS AF: 0.476

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.608

Alfa AF: 0.509 Hom.: 2786

Bravo AF: 0.648

Asia WGS AF: 0.655 AC: 2280 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Gordon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Marden-Walker syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Arthrogryposis, distal, with impaired proprioception and touch Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs8096037; hg19: chr18-10748603;