Genetic Variant PIEZO1:p.Pro2510Leu (chr16-88715642-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001142864.4(PIEZO1):c.7529C>T(p.Pro2510Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00839 in 1,550,192 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2510Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0073 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0085 ( 67 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 9.85

Publications

19 publications found

Variant links:

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 links:

CTU2 (HGNC:28005): (cytosolic thiouridylase subunit 2) This gene encodes a protein which is involved in the post-transcriptional modification of transfer RNAs (tRNAs). The encoded protein plays a role in thiolation of uridine residue present at the wobble position in a subset of tRNAs, resulting in enhanced codon reading accuracy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

CTU2 Gene-Disease associations (from GenCC):

microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

CTU2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025440753).

BP6

Variant 16-88715642-G-A is Benign according to our data. Variant chr16-88715642-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 618787.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00727 (1107/152324) while in subpopulation AMR AF = 0.0179 (274/15302). AF 95% confidence interval is 0.0162. There are 7 homozygotes in GnomAd4. There are 539 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO1	NM_001142864.4	MANE Select	c.7529C>T	p.Pro2510Leu	missense	Exon 51 of 51	NP_001136336.2	Q92508
CTU2	NM_001012759.3	MANE Select	c.*391G>A		downstream_gene	N/A	NP_001012777.1	Q2VPK5-1
CTU2	NM_001318507.2		c.*391G>A		downstream_gene	N/A	NP_001305436.1	H3BSW6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.7529C>T	p.Pro2510Leu	missense	Exon 51 of 51	ENSP00000301015.9	Q92508
PIEZO1	ENST00000419505.5	TSL:1	n.*1069C>T		non_coding_transcript_exon	Exon 10 of 10	ENSP00000406358.1	H7C2J5
PIEZO1	ENST00000419505.5	TSL:1	n.*1069C>T		3_prime_UTR	Exon 10 of 10	ENSP00000406358.1	H7C2J5

Frequencies

GnomAD3 genomes

AF:

0.00727

AC:

1107

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00982

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.00724

AC:

1118

AN:

154500

AF XY:

0.00682

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.0000919

Gnomad FIN exome

AF:

0.00133

Gnomad NFE exome

AF:

0.0107

Gnomad OTH exome

AF:

0.00985

GnomAD4 exome

AF:

0.00851

AC:

11899

AN:

1397868

Hom.:

Cov.:

AF XY:

0.00820

AC XY:

5655

AN XY:

689434

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

31598

American (AMR)

AF:

0.0120

AC:

429

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00671

AC:

169

AN:

25180

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35732

South Asian (SAS)

AF:

0.00124

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00107

AC:

AN:

47884

Middle Eastern (MID)

AF:

0.00176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00994

AC:

10721

AN:

1078860

Other (OTH)

AF:

0.00657

AC:

381

AN:

57978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

608

1216

1823

2431

3039

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00727

AC:

1107

AN:

152324

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

539

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41574

American (AMR)

AF:

0.0179

AC:

274

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00982

AC:

668

AN:

68030

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00660

Hom.:

Bravo

AF:

0.00761

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0122

AC:

ExAC

AF:

0.00345

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.025

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.2

PhyloP100

9.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-9.4

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.79

MVP

0.73

ClinPred

0.11

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.96

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over