16-88715960-G-C

Position:

• chr16-88715960-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM5 PP3 BS2

The NM_001142864.4(PIEZO1):​c.7289C>G​(p.Pro2430Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,397,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2430L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88715960-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815
• BS2: High AC in GnomAdExome4 at 41 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIEZO1	NM_001142864.4	c.7289C>G	p.Pro2430Arg	missense_variant	50/51	ENST00000301015.14	NP_001136336.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7289C>G	p.Pro2430Arg	missense_variant	50/51	1	NM_001142864.4	ENSP00000301015	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000130 AC: 2 AN: 153750 Hom.: 0 AF XY: 0.0000244 AC XY: 2 AN XY: 81894

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000170

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000293 AC: 41 AN: 1397534 Hom.: 0 Cov.: 46 AF XY: 0.0000276 AC XY: 19 AN XY: 689200

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000352

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.42		Gain of solvent accessibility (P = 0.0246);
MVP		0.34
ClinPred		0.97	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.59
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs869025601; hg19: chr16-88782368;