16-88715613-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.7558A>G(p.Lys2520Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000151 in 1,549,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.76

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=0.024006248).
• BP6: Variant 16-88715613-T-C is Benign according to our data. Variant chr16-88715613-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330570.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS2: High AC in GnomAd at 18 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO1	NM_001142864.4	c.7558A>G	p.Lys2520Glu	missense_variant	51/51	ENST00000301015.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7558A>G	p.Lys2520Glu	missense_variant	51/51	1	NM_001142864.4	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151928 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000275 AC: 42 AN: 152644 Hom.: 0 AF XY: 0.000320 AC XY: 26 AN XY: 81358

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00178

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000792

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000516

Gnomad OTH exome AF: 0.000232

GnomAD4 exome AF: 0.000154 AC: 215 AN: 1397552 Hom.: 0 Cov.: 32 AF XY: 0.000178 AC XY: 123 AN XY: 689260

Gnomad4 AFR exome AF: 0.0000950

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000694

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000362

Gnomad4 OTH exome AF: 0.000293

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74326

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.000473 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 29, 2022	BS2, BP4 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.042
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Benign	0.085	T
Sift4G	Uncertain	0.023	D
Polyphen		0.21	B
Vest4		0.38
MVP		0.19
ClinPred		0.052	T
GERP RS		3.6
Varity_R		0.18
gMVP		0.73

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: rs570744198; hg19: chr16-88782021;