chr2-208347983-G-A

Variant names:

• chr2-208347983-G-A
• rs2304545
• NM_015040.4:c.5334G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015040.4(PIKFYVE):​c.5334G>A​(p.Thr1778Thr) 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:4
• Conservation: PhyloP100: 0.549
• Publications: 25 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 333930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PIKFYVE	NM_015040.4	c.5334G>A	p.Thr1778Thr	synonymous_variant	Exon 35 of 42	ENST00000264380.9	NP_055855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIKFYVE	ENST00000264380.9	c.5334G>A	p.Thr1778Thr	synonymous_variant	Exon 35 of 42	1	NM_015040.4	ENSP00000264380.4

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

GnomAD2 exomes AF: 0.823 AC: 207006 AN: 251456 AF XY: 0.829

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 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

African (AFR) AF: 0.354 AC: 11850 AN: 33472

American (AMR) AF: 0.879 AC: 39327 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 22787 AN: 26132

East Asian (EAS) AF: 0.917 AC: 36403 AN: 39694

South Asian (SAS) AF: 0.814 AC: 70220 AN: 86252

European-Finnish (FIN) AF: 0.894 AC: 47743 AN: 53416

Middle Eastern (MID) AF: 0.826 AC: 4763 AN: 5764

European-Non Finnish (NFE) AF: 0.840 AC: 933814 AN: 1111832

Other (OTH) AF: 0.813 AC: 49102 AN: 60390

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

African (AFR) AF: 0.374 AC: 15497 AN: 41442

American (AMR) AF: 0.821 AC: 12538 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2990 AN: 3472

East Asian (EAS) AF: 0.898 AC: 4651 AN: 5182

South Asian (SAS) AF: 0.820 AC: 3953 AN: 4818

European-Finnish (FIN) AF: 0.899 AC: 9524 AN: 10596

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.837 AC: 56930 AN: 68016

Other (OTH) AF: 0.759 AC: 1602 AN: 2112

Alfa AF: 0.731 Hom.: 35412

Bravo AF: 0.696

Asia WGS AF: 0.821 AC: 2856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.9
DANN	Benign	0.64
PhyloP100		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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