2-208350862-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015040.4(PIKFYVE):c.5526A>G(p.Glu1842=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,614,090 control chromosomes in the GnomAD database, including 763,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66315 hom., cov: 31)
  • Exomes 𝑓: 0.98 (697362 hom.)
• Consequence: PIKFYVE NM_015040.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0520

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-208350862-A-G is Benign according to our data. Variant chr2-208350862-A-G is described in ClinVar as [Benign]. Clinvar id is 333934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208350862-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.052 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIKFYVE	NM_015040.4	c.5526A>G	p.Glu1842=	synonymous_variant	37/42	ENST00000264380.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIKFYVE	ENST00000264380.9	c.5526A>G	p.Glu1842=	synonymous_variant	37/42	1	NM_015040.4	P1

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141400 AN: 152104 Hom.: 66264 Cov.: 31

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.970

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.931

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.983

Gnomad OTH AF: 0.939

GnomAD3 exomes AF: 0.964 AC: 242530 AN: 251472 Hom.: 117278 AF XY: 0.966 AC XY: 131331 AN XY: 135908

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.985

Gnomad ASJ exome AF: 0.997

Gnomad EAS exome AF: 0.940

Gnomad SAS exome AF: 0.939

Gnomad FIN exome AF: 0.997

Gnomad NFE exome AF: 0.983

Gnomad OTH exome AF: 0.977

GnomAD4 exome AF: 0.976 AC: 1427077 AN: 1461868 Hom.: 697362 Cov.: 67 AF XY: 0.976 AC XY: 709758 AN XY: 727232

Gnomad4 AFR exome AF: 0.793

Gnomad4 AMR exome AF: 0.982

Gnomad4 ASJ exome AF: 0.996

Gnomad4 EAS exome AF: 0.957

Gnomad4 SAS exome AF: 0.941

Gnomad4 FIN exome AF: 0.996

Gnomad4 NFE exome AF: 0.984

Gnomad4 OTH exome AF: 0.969

GnomAD4 genome AF: 0.930 AC: 141509 AN: 152222 Hom.: 66315 Cov.: 31 AF XY: 0.932 AC XY: 69362 AN XY: 74448

Gnomad4 AFR AF: 0.800

Gnomad4 AMR AF: 0.970

Gnomad4 ASJ AF: 0.996

Gnomad4 EAS AF: 0.944

Gnomad4 SAS AF: 0.933

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.983

Gnomad4 OTH AF: 0.940

Alfa AF: 0.970 Hom.: 91248

Bravo AF: 0.922

Asia WGS AF: 0.930 AC: 3236 AN: 3478

EpiCase AF: 0.983

EpiControl AF: 0.985

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	- -

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
BayesDel_noAF	Benign	-0.53
Cadd	Benign	1.8
Dann	Benign	0.66

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: rs994697; hg19: chr2-209215586;