rs1555648288

Variant names:

• chr18-10795003-C-T
• rs1555648288
• NM_001378183.1:c.1528-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001378183.1(PIEZO2):​c.1528-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 1,546,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIEZO2 NM_001378183.1 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.57
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.026866714 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.2, offset of 1, new splice context is: ccttttctgtcctccggaAGcct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-10795003-C-T is Pathogenic according to our data. Variant chr18-10795003-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 489220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.1528-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 55	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.1528-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 55		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394666 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 687870

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078722

Other (OTH) AF: 0.00 AC: 0 AN: 58010

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Dec 07, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1528-1G>A variant in the PIEZO2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 12. It is predicted to cause abnormal gene splicing resulting in an in-frame protein product with an abnormal message. The c.1528-1G>A variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1528-1G>A as a likely pathogenic variant. -

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

Dec 11, 2017

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This splice site mutation is categorized as deleterious according to ACMG guidelines (PMID: 18414213) and was found in trans with another variant (c.5083-1G>A) in a 6-year-old female with ataxia, hypotonia, mild dysmorphic features, delayed motor development, scoliosis. It is predicted to cause abnormal gene splicing resulting in an in-frame protein product with an abnormal message. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.6
GERP RS		4.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.94		Position offset: -2
DS_AL_spliceai		0.89		Position offset: -1

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

Other links and lift over

dbSNP: rs1555648288; hg19: chr18-10795001;