rs10932258

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015040.4(PIKFYVE):c.2087G>A(p.Ser696Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,610,828 control chromosomes in the GnomAD database, including 803,335 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 75137 hom., cov: 32)

Exomes 𝑓: 1.0 ( 728198 hom. )

Consequence

PIKFYVE
NM_015040.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.52

Publications

28 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet

PIKFYVE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.648329E-7).

BP6

Variant 2-208320256-G-A is Benign according to our data. Variant chr2-208320256-G-A is described in ClinVar as Benign. ClinVar VariationId is 333897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIKFYVE	NM_015040.4 link	c.2087G>A	p.Ser696Asn	missense_variant	Exon 17 of 42	ENST00000264380.9	NP_055855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PIKFYVE	ENST00000264380.9 link	c.2087G>A	p.Ser696Asn	missense_variant	Exon 17 of 42	1	NM_015040.4	ENSP00000264380.4
PIKFYVE	ENST00000443896.5 link	n.*1438G>A		non_coding_transcript_exon_variant	Exon 16 of 19	1		ENSP00000407692.1
PIKFYVE	ENST00000443896.5 link	n.*1438G>A		3_prime_UTR_variant	Exon 16 of 19	1		ENSP00000407692.1
PIKFYVE	ENST00000452564.1 link	c.1919G>A	p.Ser640Asn	missense_variant	Exon 16 of 25	2		ENSP00000405736.1

Frequencies

GnomAD3 genomes

AF:

0.993

AC:

151171

AN:

152208

Hom.:

75082

Cov.:

show subpopulations

Gnomad AFR

AF:

0.976

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.997

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.997

GnomAD2 exomes

AF:

0.998

AC:

249202

AN:

249662

AF XY:

0.999

show subpopulations

Gnomad AFR exome

AF:

0.975

Gnomad AMR exome

AF:

0.999

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.999

GnomAD4 exome

AF:

0.999

AC:

1457438

AN:

1458502

Hom.:

728198

Cov.:

AF XY:

0.999

AC XY:

725074

AN XY:

725522

show subpopulations

African (AFR)

AF:

0.975

AC:

32547

AN:

33372

American (AMR)

AF:

0.998

AC:

44451

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26037

AN:

26038

East Asian (EAS)

AF:

1.00

AC:

39452

AN:

39452

South Asian (SAS)

AF:

1.00

AC:

85709

AN:

85718

European-Finnish (FIN)

AF:

1.00

AC:

53348

AN:

53350

Middle Eastern (MID)

AF:

0.998

AC:

5657

AN:

5668

European-Non Finnish (NFE)

AF:

1.00

AC:

1110092

AN:

1110140

Other (OTH)

AF:

0.998

AC:

60145

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21644

43288

64932

86576

108220

<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:

0.993

AC:

151285

AN:

152326

Hom.:

75137

Cov.:

AF XY:

0.994

AC XY:

74009

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.976

AC:

40596

AN:

41576

American (AMR)

AF:

0.997

AC:

15251

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5180

AN:

5180

South Asian (SAS)

AF:

1.00

AC:

4826

AN:

4826

European-Finnish (FIN)

AF:

1.00

AC:

10621

AN:

10622

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68026

AN:

68034

Other (OTH)

AF:

0.997

AC:

2107

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.998

Hom.:

63818

Bravo

AF:

0.992

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.977

AC:

4305

ESP6500EA

AF:

1.00

AC:

8589

ExAC

AF:

0.998

AC:

121099

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Fleck corneal dystrophy

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.24

T;T

MetaRNN

Benign

5.6e-7

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.77

N;.

PhyloP100

7.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.65

N;N

REVEL

Benign

0.29

Sift

Benign

1.0

T;T

Sift4G

Benign

0.86

T;T

Vest4

0.039

ClinPred

0.022

GERP RS

5.8

Varity_R

0.20

gMVP

0.18

Mutation Taster

=92/8

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over