18-10731392-C-G

Variant names:

• chr18-10731392-C-G
• rs78691268
• NM_001378183.1:c.5029+15G>C

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.5029+15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 1,518,384 control chromosomes in the GnomAD database, including 4,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (398 hom., cov: 28)
  • Exomes 𝑓: 0.073 (3926 hom.)
• Consequence: PIEZO2 NM_001378183.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.865
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• arthrogryposis, distal, with impaired proprioception and touch

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• connective tissue disorder

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Marden-Walker syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-10731392-C-G is Benign according to our data. Variant chr18-10731392-C-G is described in ClinVar as Benign. ClinVar VariationId is 261512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0771 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.5029+15G>C		intron	N/A	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.4930+15G>C		intron	N/A	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.4855+15G>C		intron	N/A	NP_071351.2	Q9H5I5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.5029+15G>C		intron	N/A	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.4855+15G>C		intron	N/A	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.4930+15G>C		intron	N/A	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.0699 AC: 10593 AN: 151614 Hom.: 399 Cov.: 28

Gnomad AFR AF: 0.0794

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0524

Gnomad ASJ AF: 0.0621

Gnomad EAS AF: 0.00464

Gnomad SAS AF: 0.0467

Gnomad FIN AF: 0.0969

Gnomad MID AF: 0.0353

Gnomad NFE AF: 0.0719

Gnomad OTH AF: 0.0662

GnomAD2 exomes AF: 0.0588 AC: 7974 AN: 135560 AF XY: 0.0584

Gnomad AFR exome AF: 0.0815

Gnomad AMR exome AF: 0.0463

Gnomad ASJ exome AF: 0.0580

Gnomad EAS exome AF: 0.00257

Gnomad FIN exome AF: 0.0918

Gnomad NFE exome AF: 0.0719

Gnomad OTH exome AF: 0.0638

GnomAD4 exome AF: 0.0734 AC: 100345 AN: 1366654 Hom.: 3926 Cov.: 26 AF XY: 0.0727 AC XY: 49105 AN XY: 675258

African (AFR) AF: 0.0845 AC: 2608 AN: 30880

American (AMR) AF: 0.0509 AC: 1761 AN: 34564

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 1476 AN: 24958

East Asian (EAS) AF: 0.00131 AC: 46 AN: 35236

South Asian (SAS) AF: 0.0475 AC: 3711 AN: 78108

European-Finnish (FIN) AF: 0.0891 AC: 3104 AN: 34848

Middle Eastern (MID) AF: 0.0365 AC: 206 AN: 5648

European-Non Finnish (NFE) AF: 0.0785 AC: 83601 AN: 1065210

Other (OTH) AF: 0.0670 AC: 3832 AN: 57202

GnomAD4 genome AF: 0.0698 AC: 10594 AN: 151730 Hom.: 398 Cov.: 28 AF XY: 0.0697 AC XY: 5165 AN XY: 74148

African (AFR) AF: 0.0794 AC: 3286 AN: 41382

American (AMR) AF: 0.0522 AC: 795 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.0621 AC: 215 AN: 3464

East Asian (EAS) AF: 0.00465 AC: 24 AN: 5162

South Asian (SAS) AF: 0.0457 AC: 219 AN: 4796

European-Finnish (FIN) AF: 0.0969 AC: 1015 AN: 10478

Middle Eastern (MID) AF: 0.0379 AC: 11 AN: 290

European-Non Finnish (NFE) AF: 0.0719 AC: 4882 AN: 67898

Other (OTH) AF: 0.0650 AC: 137 AN: 2108

Alfa AF: 0.0437 Hom.: 35

Bravo AF: 0.0669

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-0.86
Mutation Taster		=100/0	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: rs78691268; hg19: chr18-10731390;