chr2-208347983-G-A
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1
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
NM_015040.4 synonymous
Scores
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 108730AN: 152010Hom.: 42341 Cov.: 32
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GnomAD3 exomes AF: 0.823 AC: 207006AN: 251456Hom.: 87189 AF XY: 0.829 AC XY: 112647AN XY: 135904
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GnomAD4 exome AF: 0.832 AC: 1216009AN: 1461672Hom.: 510425 Cov.: 61 AF XY: 0.833 AC XY: 605774AN XY: 727174
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GnomAD4 genome AF: 0.715 AC: 108765AN: 152124Hom.: 42354 Cov.: 32 AF XY: 0.723 AC XY: 53768AN XY: 74390
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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
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BayesDel_noAF
Benign
CADD
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DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at