chr16-88715693-A-AGCTCCC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3BP3BP6BS1

The NM_001142864.4(PIEZO1):c.7472_7477dupGGGAGC(p.Arg2491_Glu2492dup) variant causes a conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000677 in 1,550,262 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 1 hom. )

Consequence

PIEZO1
NM_001142864.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.96

Publications

1 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 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
dehydrated hereditary stomatocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIEZO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP3

Nonframeshift variant in repetitive region in NM_001142864.4

BP6

Variant 16-88715693-A-AGCTCCC is Benign according to our data. Variant chr16-88715693-A-AGCTCCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1328215.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000565 (86/152226) while in subpopulation NFE AF = 0.000896 (61/68044). AF 95% confidence interval is 0.000716. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	NM_001142864.4	MANE Select	c.7472_7477dupGGGAGC	p.Arg2491_Glu2492dup	conservative_inframe_insertion	Exon 51 of 51	NP_001136336.2	Q92508

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.7472_7477dupGGGAGC	p.Arg2491_Glu2492dup	conservative_inframe_insertion	Exon 51 of 51	ENSP00000301015.9	Q92508
PIEZO1	ENST00000419505.5	TSL:1	n.1012_1017dupGGGAGC		non_coding_transcript_exon	Exon 10 of 10	ENSP00000406358.1	H7C2J5
PIEZO1	ENST00000419505.5	TSL:1	n.1012_1017dupGGGAGC		3_prime_UTR	Exon 10 of 10	ENSP00000406358.1	H7C2J5

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000896

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000641

AC:

100

AN:

156038

AF XY:

0.000616

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000918

Gnomad FIN exome

AF:

0.00214

Gnomad NFE exome

AF:

0.000782

Gnomad OTH exome

AF:

0.000455

GnomAD4 exome

AF:

0.000690

AC:

964

AN:

1398036

Hom.:

Cov.:

AF XY:

0.000677

AC XY:

467

AN XY:

689502

show subpopulations

African (AFR)

AF:

0.000222

AC:

AN:

31594

American (AMR)

AF:

0.000224

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.000278

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00156

AC:

AN:

47964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000759

AC:

819

AN:

1078928

Other (OTH)

AF:

0.000552

AC:

AN:

57996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000565

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000896

AC:

AN:

68044

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000632

Hom.:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Lymphatic malformation 6;C4551512:Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=58/42

polymorphism

(source)

Splicing

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