rs10932258

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000264380.9(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. 13/20 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
ENST00000264380.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.52

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIKFYVE. . Gene score misZ 2.0469 (greater than the threshold 3.09). Trascript score misZ 3.5403 (greater than threshold 3.09). GenCC has associacion of gene with fleck corneal dystrophy.

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 id is 333897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208320256-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PIKFYVE	NM_015040.4 linkuse as main transcript	c.2087G>A	p.Ser696Asn	missense_variant	17/42	ENST00000264380.9	NP_055855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIKFYVE	ENST00000264380.9 linkuse as main transcript	c.2087G>A	p.Ser696Asn	missense_variant	17/42	1	NM_015040.4	ENSP00000264380	P1	Q9Y2I7-1
PIKFYVE	ENST00000443896.5 linkuse as main transcript	c.*1438G>A		3_prime_UTR_variant, NMD_transcript_variant	16/19	1		ENSP00000407692
PIKFYVE	ENST00000452564.1 linkuse as main transcript	c.1919G>A	p.Ser640Asn	missense_variant	16/25	2		ENSP00000405736

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

GnomAD3 exomes

AF:

0.998

AC:

249202

AN:

249662

Hom.:

124376

AF XY:

0.999

AC XY:

134792

AN XY:

134972

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 SAS 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

Gnomad4 AFR exome

AF:

0.975

Gnomad4 AMR exome

AF:

0.998

Gnomad4 ASJ exome

AF:

1.00

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

1.00

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.998

GnomAD4 genome

AF:

0.993

AC:

151285

AN:

152326

Hom.:

75137

Cov.:

AF XY:

0.994

AC XY:

74009

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.976

Gnomad4 AMR

AF:

0.997

Gnomad4 ASJ

AF:

1.00

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

1.00

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

1.00

Gnomad4 OTH

AF:

0.997

Alfa

AF:

0.998

Hom.:

63145

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Fleck corneal dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

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

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;.

MutationTaster

Benign

1.0

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

Polyphen

0.0

B;B

Vest4

0.039

MPC

0.27

ClinPred

0.022

GERP RS

5.8

Varity_R

0.20

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over