2-208325795-A-T

Variant names:

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.2984A>T(p.Gln995Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,613,742 control chromosomes in the GnomAD database, including 763,631 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 66252 hom., cov: 31)

Exomes 𝑓: 0.98 ( 697379 hom. )

Consequence

PIKFYVE
NM_015040.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.44

Publications

30 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=1.1307615E-6).

BP6

Variant 2-208325795-A-T is Benign according to our data. Variant chr2-208325795-A-T is described in ClinVar as Benign. ClinVar VariationId is 333909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIKFYVE	NM_015040.4 link	c.2984A>T	p.Gln995Leu	missense_variant	Exon 20 of 42	ENST00000264380.9	NP_055855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PIKFYVE	ENST00000264380.9 link	c.2984A>T	p.Gln995Leu	missense_variant	Exon 20 of 42	1	NM_015040.4	ENSP00000264380.4
PIKFYVE	ENST00000443896.5 link	n.*2335A>T		non_coding_transcript_exon_variant	Exon 19 of 19	1		ENSP00000407692.1
PIKFYVE	ENST00000443896.5 link	n.*2335A>T		3_prime_UTR_variant	Exon 19 of 19	1		ENSP00000407692.1
PIKFYVE	ENST00000452564.1 link	c.2816A>T	p.Gln939Leu	missense_variant	Exon 19 of 25	2		ENSP00000405736.1

Frequencies

GnomAD3 genomes

AF:

0.930

AC:

141237

AN:

151878

Hom.:

66200

Cov.:

show subpopulations

Gnomad AFR

AF:

0.801

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.970

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

0.943

Gnomad SAS

AF:

0.932

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:

241668

AN:

250574

AF XY:

0.966

show subpopulations

Gnomad AFR exome

AF:

0.799

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:

0.978

GnomAD4 exome

AF:

0.976

AC:

1427050

AN:

1461746

Hom.:

697379

Cov.:

AF XY:

0.976

AC XY:

709734

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.796

AC:

26621

AN:

33464

American (AMR)

AF:

0.982

AC:

43927

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

26026

AN:

26122

East Asian (EAS)

AF:

0.957

AC:

37976

AN:

39696

South Asian (SAS)

AF:

0.941

AC:

81162

AN:

86246

European-Finnish (FIN)

AF:

0.996

AC:

53190

AN:

53418

Middle Eastern (MID)

AF:

0.964

AC:

5559

AN:

5766

European-Non Finnish (NFE)

AF:

0.984

AC:

1094072

AN:

1111934

Other (OTH)

AF:

0.969

AC:

58517

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

2012

4025

6037

8050

10062

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:

141347

AN:

151996

Hom.:

66252

Cov.:

AF XY:

0.932

AC XY:

69244

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.801

AC:

33131

AN:

41346

American (AMR)

AF:

0.970

AC:

14832

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

3449

AN:

3464

East Asian (EAS)

AF:

0.943

AC:

4859

AN:

5150

South Asian (SAS)

AF:

0.933

AC:

4492

AN:

4816

European-Finnish (FIN)

AF:

0.997

AC:

10580

AN:

10610

Middle Eastern (MID)

AF:

0.973

AC:

286

AN:

294

European-Non Finnish (NFE)

AF:

0.983

AC:

66827

AN:

68000

Other (OTH)

AF:

0.940

AC:

1983

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

453

905

1358

1810

2263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.977

Hom.:

54249

Bravo

AF:

0.922

TwinsUK

AF:

0.986

AC:

3657

ALSPAC

AF:

0.984

AC:

3794

ESP6500AA

AF:

0.807

AC:

3554

ESP6500EA

AF:

0.982

AC:

8442

ExAC

AF:

0.960

AC:

116496

Asia WGS

AF:

0.930

AC:

3235

AN:

3478

EpiCase

AF:

0.983

EpiControl

AF:

0.984

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 28, 2022

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Fleck corneal dystrophy

Benign:2

Jan 12, 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

0.072

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.61

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.42

T;T

MetaRNN

Benign

0.0000011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;.

PhyloP100

1.4

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.040

Sift

Benign

0.096

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

B;B

Vest4

0.10

MPC

0.28

ClinPred

0.0086

GERP RS

4.2

Varity_R

0.085

gMVP

0.22

Mutation Taster

=90/10

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