rs2118297

Variant names:

• chr2-208350046-A-G
• rs2118297
• NM_015040.4:c.5397A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-208350046-A-G
• chr2-208350046-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015040.4(PIKFYVE):​c.5397A>G​(p.Thr1799Thr) 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 1,611,464 control chromosomes in the GnomAD database, including 762,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66259 hom., cov: 31)
  • Exomes 𝑓: 0.98 (696154 hom.)
• Consequence: PIKFYVE NM_015040.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.87
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-208350046-A-G is Benign according to our data. Variant chr2-208350046-A-G is described in ClinVar as Benign. ClinVar VariationId is 333932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIKFYVE	NM_015040.4	c.5397A>G	p.Thr1799Thr	synonymous_variant	Exon 36 of 42	ENST00000264380.9	NP_055855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIKFYVE	ENST00000264380.9	c.5397A>G	p.Thr1799Thr	synonymous_variant	Exon 36 of 42	1	NM_015040.4	ENSP00000264380.4

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141301 AN: 152010 Hom.: 66208 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: 0.943

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

GnomAD2 exomes AF: 0.964 AC: 241826 AN: 250756 AF XY: 0.966

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 FIN exome AF: 0.997

Gnomad NFE exome AF: 0.983

Gnomad OTH exome AF: 0.977

GnomAD4 exome AF: 0.976 AC: 1424603 AN: 1459336 Hom.: 696154 Cov.: 85 AF XY: 0.976 AC XY: 708565 AN XY: 726010

African (AFR) AF: 0.793 AC: 26503 AN: 33414

American (AMR) AF: 0.982 AC: 43839 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 25941 AN: 26036

East Asian (EAS) AF: 0.957 AC: 37786 AN: 39500

South Asian (SAS) AF: 0.941 AC: 81004 AN: 86082

European-Finnish (FIN) AF: 0.996 AC: 53059 AN: 53286

Middle Eastern (MID) AF: 0.964 AC: 5540 AN: 5748

European-Non Finnish (NFE) AF: 0.984 AC: 1092554 AN: 1110398

Other (OTH) AF: 0.969 AC: 58377 AN: 60248

GnomAD4 genome AF: 0.930 AC: 141410 AN: 152128 Hom.: 66259 Cov.: 31 AF XY: 0.932 AC XY: 69324 AN XY: 74416

African (AFR) AF: 0.800 AC: 33189 AN: 41468

American (AMR) AF: 0.970 AC: 14833 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3457 AN: 3472

East Asian (EAS) AF: 0.943 AC: 4889 AN: 5182

South Asian (SAS) AF: 0.933 AC: 4491 AN: 4816

European-Finnish (FIN) AF: 0.997 AC: 10560 AN: 10590

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.983 AC: 66813 AN: 67986

Other (OTH) AF: 0.939 AC: 1984 AN: 2112

Alfa AF: 0.972 Hom.: 111844

Bravo AF: 0.922

Asia WGS AF: 0.930 AC: 3230 AN: 3474

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	-0.59
CADD	Benign	9.8
DANN	Benign	0.69
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2118297; hg19: chr2-209214770; COSMIC: COSV108051668;