rs2304545

Positions:

• chr2-208347983-G-A
• chr2-208347983-G-C
• chr2-208347983-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015040.4(PIKFYVE):​c.5334G>A​(p.Thr1778=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 1,613,796 control chromosomes in the GnomAD database, including 552,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (42354 hom., cov: 32)
  • Exomes 𝑓: 0.83 (510425 hom.)
• Consequence: PIKFYVE NM_015040.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.549

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 2-208347983-G-A is Benign according to our data. Variant chr2-208347983-G-A is described in ClinVar as [Benign]. Clinvar id is 333930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208347983-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.549 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIKFYVE	NM_015040.4	c.5334G>A	p.Thr1778=	synonymous_variant	35/42	ENST00000264380.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIKFYVE	ENST00000264380.9	c.5334G>A	p.Thr1778=	synonymous_variant	35/42	1	NM_015040.4	P1

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108730 AN: 152010 Hom.: 42341 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.898

Gnomad SAS AF: 0.818

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.756

GnomAD3 exomes AF: 0.823 AC: 207006 AN: 251456 Hom.: 87189 AF XY: 0.829 AC XY: 112647 AN XY: 135904

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.887

Gnomad ASJ exome AF: 0.868

Gnomad EAS exome AF: 0.900

Gnomad SAS exome AF: 0.812

Gnomad FIN exome AF: 0.898

Gnomad NFE exome AF: 0.841

Gnomad OTH exome AF: 0.840

GnomAD4 exome AF: 0.832 AC: 1216009 AN: 1461672 Hom.: 510425 Cov.: 61 AF XY: 0.833 AC XY: 605774 AN XY: 727174

Gnomad4 AFR exome AF: 0.354

Gnomad4 AMR exome AF: 0.879

Gnomad4 ASJ exome AF: 0.872

Gnomad4 EAS exome AF: 0.917

Gnomad4 SAS exome AF: 0.814

Gnomad4 FIN exome AF: 0.894

Gnomad4 NFE exome AF: 0.840

Gnomad4 OTH exome AF: 0.813

GnomAD4 genome AF: 0.715 AC: 108765 AN: 152124 Hom.: 42354 Cov.: 32 AF XY: 0.723 AC XY: 53768 AN XY: 74390

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.821

Gnomad4 ASJ AF: 0.861

Gnomad4 EAS AF: 0.898

Gnomad4 SAS AF: 0.820

Gnomad4 FIN AF: 0.899

Gnomad4 NFE AF: 0.837

Gnomad4 OTH AF: 0.759

Alfa AF: 0.767 Hom.: 25872

Bravo AF: 0.696

Asia WGS AF: 0.821 AC: 2856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fleck corneal dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.9
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2304545; hg19: chr2-209212707; COSMIC: COSV52250235;