2-208325908-T-G

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.3097T>G(p.Ser1033Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,612,464 control chromosomes in the GnomAD database, including 15,306 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 0.13 ( 1411 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13895 hom. )

Consequence

PIKFYVE
NM_015040.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.81

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=0.001552254).

BP6

Variant 2-208325908-T-G is Benign according to our data. Variant chr2-208325908-T-G is described in ClinVar as Benign. ClinVar VariationId is 333911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIKFYVE	NM_015040.4 link	c.3097T>G	p.Ser1033Ala	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.3097T>G	p.Ser1033Ala	missense_variant	Exon 20 of 42	1	NM_015040.4	ENSP00000264380.4
PIKFYVE	ENST00000443896.5 link	n.*2448T>G		non_coding_transcript_exon_variant	Exon 19 of 19	1		ENSP00000407692.1
PIKFYVE	ENST00000443896.5 link	n.*2448T>G		3_prime_UTR_variant	Exon 19 of 19	1		ENSP00000407692.1
PIKFYVE	ENST00000452564.1 link	c.2929T>G	p.Ser977Ala	missense_variant	Exon 19 of 25	2		ENSP00000405736.1

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20063

AN:

152068

Hom.:

1412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.0747

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.0125

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0985

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.145

Gnomad OTH

AF:

0.131

GnomAD2 exomes

AF:

0.117

AC:

29323

AN:

251002

AF XY:

0.119

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.0821

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.00701

Gnomad FIN exome

AF:

0.0985

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.134

AC:

196232

AN:

1460276

Hom.:

13895

Cov.:

AF XY:

0.134

AC XY:

97656

AN XY:

726524

show subpopulations

African (AFR)

AF:

0.142

AC:

4764

AN:

33450

American (AMR)

AF:

0.0862

AC:

3856

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

3242

AN:

26126

East Asian (EAS)

AF:

0.0121

AC:

482

AN:

39696

South Asian (SAS)

AF:

0.125

AC:

10818

AN:

86232

European-Finnish (FIN)

AF:

0.102

AC:

5454

AN:

53410

Middle Eastern (MID)

AF:

0.121

AC:

696

AN:

5768

European-Non Finnish (NFE)

AF:

0.143

AC:

158800

AN:

1110548

Other (OTH)

AF:

0.135

AC:

8120

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

10053

20106

30158

40211

50264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5644

11288

16932

22576

28220

<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:

0.132

AC:

20064

AN:

152188

Hom.:

1411

Cov.:

AF XY:

0.128

AC XY:

9544

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.143

AC:

5953

AN:

41516

American (AMR)

AF:

0.117

AC:

1784

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

467

AN:

3468

East Asian (EAS)

AF:

0.0126

AC:

AN:

5176

South Asian (SAS)

AF:

0.111

AC:

533

AN:

4812

European-Finnish (FIN)

AF:

0.0985

AC:

1045

AN:

10604

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.145

AC:

9840

AN:

67994

Other (OTH)

AF:

0.129

AC:

272

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

924

1848

2772

3696

4620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.138

Hom.:

6632

Bravo

AF:

0.132

TwinsUK

AF:

0.150

AC:

555

ALSPAC

AF:

0.145

AC:

560

ESP6500AA

AF:

0.143

AC:

629

ESP6500EA

AF:

0.140

AC:

1207

ExAC

AF:

0.120

AC:

14619

Asia WGS

AF:

0.0790

AC:

277

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fleck corneal dystrophy

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.82

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.53

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;.

PhyloP100

2.8

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.48

N;N

REVEL

Benign

0.10

Sift

Benign

0.20

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.089

B;B

Vest4

0.049

MPC

0.27

ClinPred

0.013

GERP RS

-0.48

Varity_R

0.032

gMVP

0.30

Mutation Taster

=77/23

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