rs994697

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015040.4(PIKFYVE):c.5526A>G(p.Glu1842Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,614,090 control chromosomes in the GnomAD database, including 763,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 66315 hom., cov: 31)

Exomes 𝑓: 0.98 ( 697362 hom. )

Consequence

PIKFYVE
NM_015040.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0520

Publications

25 publications found

Variant links:

Genes affected

PIKFYVE (HGNC:23785): (phosphoinositide kinase, FYVE-type zinc finger containing) Phosphorylated derivatives of phosphatidylinositol (PtdIns) regulate cytoskeletal functions, membrane trafficking, and receptor signaling by recruiting protein complexes to cell- and endosomal-membranes. Humans have multiple PtdIns proteins that differ by the degree and position of phosphorylation of the inositol ring. This gene encodes an enzyme (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) that phosphorylates the D-5 position in PtdIns and phosphatidylinositol-3-phosphate (PtdIns3P) to make PtdIns5P and PtdIns(3,5)biphosphate. The D-5 position also can be phosphorylated by type I PtdIns4P-5-kinases (PIP5Ks) that are encoded by distinct genes and preferentially phosphorylate D-4 phosphorylated PtdIns. In contrast, PIKfyve preferentially phosphorylates D-3 phosphorylated PtdIns. In addition to being a lipid kinase, PIKfyve also has protein kinase activity. PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosome carrier vesicles from early endosomes. The protein plays a key role in cell entry of ebola virus and SARS-CoV-2 by endocytosis Mutations in this gene cause corneal fleck dystrophy (CFD); an autosomal dominant disorder characterized by numerous small white flecks present in all layers of the corneal stroma. Histologically, these flecks appear to be keratocytes distended with lipid and mucopolysaccharide filled intracytoplasmic vacuoles. [provided by RefSeq, Jul 2021]

PIKFYVE Gene-Disease associations (from GenCC):

fleck corneal dystrophy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

PIKFYVE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 2-208350862-A-G is Benign according to our data. Variant chr2-208350862-A-G is described in ClinVar as Benign. ClinVar VariationId is 333934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.052 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015040.4. 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
	PIKFYVE	NM_015040.4	MANE Select	c.5526A>G	p.Glu1842Glu	synonymous	Exon 37 of 42	NP_055855.2	Q9Y2I7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIKFYVE	ENST00000264380.9	TSL:1 MANE Select	c.5526A>G	p.Glu1842Glu	synonymous	Exon 37 of 42	ENSP00000264380.4	Q9Y2I7-1
PIKFYVE	ENST00000909798.1		c.5541A>G	p.Glu1847Glu	synonymous	Exon 38 of 43	ENSP00000579857.1
PIKFYVE	ENST00000923116.1		c.5508A>G	p.Glu1836Glu	synonymous	Exon 37 of 42	ENSP00000593175.1

Frequencies

GnomAD3 genomes

AF:

0.930

AC:

141400

AN:

152104

Hom.:

66264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.800

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.970

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

0.944

Gnomad SAS

AF:

0.931

Gnomad FIN

AF:

0.997

Gnomad MID

AF:

0.975

Gnomad NFE

AF:

0.983

Gnomad OTH

AF:

0.939

GnomAD2 exomes

AF:

0.964

AC:

242530

AN:

251472

AF XY:

0.966

show subpopulations

Gnomad AFR exome

AF:

0.798

Gnomad AMR exome

AF:

0.985

Gnomad ASJ exome

AF:

0.997

Gnomad EAS exome

AF:

0.940

Gnomad FIN exome

AF:

0.997

Gnomad NFE exome

AF:

0.983

Gnomad OTH exome

AF:

0.977

GnomAD4 exome

AF:

0.976

AC:

1427077

AN:

1461868

Hom.:

697362

Cov.:

AF XY:

0.976

AC XY:

709758

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.793

AC:

26564

AN:

33478

American (AMR)

AF:

0.982

AC:

43933

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

26040

AN:

26136

East Asian (EAS)

AF:

0.957

AC:

37977

AN:

39696

South Asian (SAS)

AF:

0.941

AC:

81169

AN:

86258

European-Finnish (FIN)

AF:

0.996

AC:

53192

AN:

53420

Middle Eastern (MID)

AF:

0.964

AC:

5549

AN:

5756

European-Non Finnish (NFE)

AF:

0.984

AC:

1094135

AN:

1112008

Other (OTH)

AF:

0.969

AC:

58518

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

2107

4214

6322

8429

10536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21650

43300

64950

86600

108250

<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:

0.930

AC:

141509

AN:

152222

Hom.:

66315

Cov.:

AF XY:

0.932

AC XY:

69362

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.800

AC:

33197

AN:

41474

American (AMR)

AF:

0.970

AC:

14843

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

3455

AN:

3470

East Asian (EAS)

AF:

0.944

AC:

4890

AN:

5180

South Asian (SAS)

AF:

0.933

AC:

4495

AN:

4820

European-Finnish (FIN)

AF:

0.997

AC:

10590

AN:

10620

Middle Eastern (MID)

AF:

0.973

AC:

286

AN:

294

European-Non Finnish (NFE)

AF:

0.983

AC:

66859

AN:

68034

Other (OTH)

AF:

0.940

AC:

1988

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

449

897

1346

1794

2243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.966

Hom.:

111333

Bravo

AF:

0.922

Asia WGS

AF:

0.930

AC:

3236

AN:

3478

EpiCase

AF:

0.983

EpiControl

AF:

0.985

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Fleck corneal dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.8

(source)

DANN

Benign

0.66

PhyloP100

-0.052

Mutation Taster

=97/3

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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