16-88715682-CCTCCAG-CCTCCAGCTCCAG

Variant names:

• chr16-88715682-C-CCTCCAG
• rs587776992
• NM_001142864.4:c.7483_7488dupCTGGAG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP3

The NM_001142864.4(PIEZO1):​c.7483_7488dupCTGGAG​(p.Glu2496_Glu2497insLeuGlu) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000566382: Published functional studies demonstrate a damaging effect on channel activity by slowing deactivation after stimulation (PMID:28716860)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIEZO1 NM_001142864.4 conservative_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.425
• Publications: 3 publications found

Genes affected

PIEZO1 (HGNC:28993): (piezo type mechanosensitive ion channel component 1 (Er blood group)) The protein encoded by this gene is a mechanically-activated ion channel that links mechanical forces to biological signals. The encoded protein contains 36 transmembrane domains and functions as a homotetramer. Defects in this gene have been associated with dehydrated hereditary stomatocytosis. [provided by RefSeq, Jul 2015]

PIEZO1 Gene-Disease associations (from GenCC):

• PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema

  Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• lymphatic malformation 6

  Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000566382: Published functional studies demonstrate a damaging effect on channel activity by slowing deactivation after stimulation (PMID: 28716860); SCV003443663: Experimental studies have shown that this variant affects PIEZO1 function (PMID: 23695678).; SCV003799968: Functional analyses of this variant show gain of PIEZO1 protein function leading to altered mechanotransduction activity of the membrane pore channel (Glogowska 2017). PMID: 28716860; SCV000996062: Functional studies demonstrate that this is a gain-of-function variant, as it leads to increased cell permeability that results in the loss of potassium and subsequent dehydration (PMID: 23695678).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-88715682-C-CCTCCAG is Pathogenic according to our data. Variant chr16-88715682-C-CCTCCAG is described in ClinVar as Pathogenic. ClinVar VariationId is 418948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_001142864.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142864.4. 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
	PIEZO1	NM_001142864.4	MANE Select	c.7483_7488dupCTGGAG	p.Glu2496_Glu2497insLeuGlu	conservative_inframe_insertion	Exon 51 of 51	NP_001136336.2	Q92508

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.7483_7488dupCTGGAG	p.Glu2496_Glu2497insLeuGlu	conservative_inframe_insertion	Exon 51 of 51	ENSP00000301015.9	Q92508
	PIEZO1	ENST00000419505.5	TSL:1	n.*1023_*1028dupCTGGAG		non_coding_transcript_exon	Exon 10 of 10	ENSP00000406358.1	H7C2J5
	PIEZO1	ENST00000419505.5	TSL:1	n.*1023_*1028dupCTGGAG		3_prime_UTR	Exon 10 of 10	ENSP00000406358.1	H7C2J5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
2	-	-	Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema (2)
1	-	-	Lymphatic malformation 6 (1)
1	-	-	Lymphatic malformation 6;C4551512:Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema;C5703066:Blood group, ER (1)
1	-	-	PIEZO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=50/50	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587776992; hg19: chr16-88782090;