16-88715666-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001142864.4(PIEZO1):c.7505A>G(p.Lys2502Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00581 in 1,550,310 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (48 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.84

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009955108).
• BP6: Variant 16-88715666-T-C is Benign according to our data. Variant chr16-88715666-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 710278.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}. Variant chr16-88715666-T-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 862 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO1	NM_001142864.4	c.7505A>G	p.Lys2502Arg	missense_variant	51/51	ENST00000301015.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7505A>G	p.Lys2502Arg	missense_variant	51/51	1	NM_001142864.4	P1

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 862 AN: 152204 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00598

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00608 AC: 946 AN: 155478 Hom.: 14 AF XY: 0.00544 AC XY: 449 AN XY: 82594

Gnomad AFR exome AF: 0.000382

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.00480

GnomAD4 exome AF: 0.00583 AC: 8144 AN: 1397988 Hom.: 48 Cov.: 33 AF XY: 0.00562 AC XY: 3878 AN XY: 689490

Gnomad4 AFR exome AF: 0.000506

Gnomad4 AMR exome AF: 0.00274

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000252

Gnomad4 FIN exome AF: 0.0291

Gnomad4 NFE exome AF: 0.00583

Gnomad4 OTH exome AF: 0.00478

GnomAD4 genome AF: 0.00566 AC: 862 AN: 152322 Hom.: 2 Cov.: 33 AF XY: 0.00654 AC XY: 487 AN XY: 74476

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0330

Gnomad4 NFE AF: 0.00598

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00491 Hom.: 1

Bravo AF: 0.00283

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00467 AC: 18

ExAC AF: 0.00392 AC: 103

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	PIEZO1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 24, 2023	BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

PIEZO1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.010	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.55
MVP		0.36
ClinPred		0.035	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs34830861; hg19: chr16-88782074; COSMIC: COSV105821912; COSMIC: COSV105821912;