rs587776988

Variant names:

• chr16-88715804-C-G
• rs587776988
• NM_001142864.4:c.7367G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-88715804-C-G
• chr16-88715804-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001142864.4(PIEZO1):​c.7367G>C​(p.Arg2456Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2456H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.00
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88715804-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 55806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 16-88715804-C-G is Pathogenic according to our data. Variant chr16-88715804-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3235926.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4	c.7367G>C	p.Arg2456Pro	missense_variant	Exon 51 of 51	ENST00000301015.14	NP_001136336.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7367G>C	p.Arg2456Pro	missense_variant	Exon 51 of 51	1	NM_001142864.4	ENSP00000301015.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema Pathogenic:1

Aug 20, 2021

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The de novo c.7367G>C (p.Arg2456Pro) missense variant identified in PIEZO1 has not been reported in affected individuals in the literature. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools (CADD score = 32, REVEL score = 0.813). A different missense variant (p.Arg2456His) affecting the same Arg2456 residue has been reported in multiple unrelated individuals as well as in large families affected with autosomal dominant dehydrated hereditary stomatocytosis and/or hereditary xerocytosis with fetal hydrops [PMID: 22529292, 23581886, 24314002, 23973043, 29396846, 31624108]. Functional studies have shown that the p.Arg2456His results in gain-of-function of the PIEZO1 channel [23695678, 23479567, 23487776, 28716860]. Another missense variant (p.Arg2456Cys) affecting the same Arg2456 has been reported as homozygous in a patient with autosomal recessive non-immune hydrops fetalis, generalized oedema at birth, and bilateral pleural effusions [PMID: 26333996]. Given the de novo status of c.7367G>C (p.Arg2456Pro), it’s absence from public databases, and published functional importance of the Arg2456 residue, the de novo c.7367G>C (p.Arg2456Pro) missense variant identified in PIEZO1 is reported as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.67		Loss of MoRF binding (P = 0.0568);
MVP		0.66
ClinPred		1.0	D
GERP RS		3.9
PromoterAI		0.017	Neutral
Varity_R		0.96
gMVP		0.98
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587776988; hg19: chr16-88782212;