NM_015040.4:c.2993C>G

Variant names:

• chr2-208325804-C-G
• rs893253
• NM_015040.4:c.2993C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015040.4(PIKFYVE):​c.2993C>G​(p.Thr998Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,613,816 control chromosomes in the GnomAD database, including 764,069 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66349 hom., cov: 30)
  • Exomes 𝑓: 0.98 (697720 hom.)
• Consequence: PIKFYVE NM_015040.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0190
• Publications: 29 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6278725E-6).
• BP6: Variant 2-208325804-C-G is Benign according to our data. Variant chr2-208325804-C-G is described in ClinVar as Benign. ClinVar VariationId is 333910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015040.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIKFYVE	NM_015040.4	MANE Select	c.2993C>G	p.Thr998Ser	missense	Exon 20 of 42	NP_055855.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIKFYVE	ENST00000264380.9	TSL:1 MANE Select	c.2993C>G	p.Thr998Ser	missense	Exon 20 of 42	ENSP00000264380.4
	PIKFYVE	ENST00000443896.5	TSL:1	n.*2344C>G		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407692.1
	PIKFYVE	ENST00000443896.5	TSL:1	n.*2344C>G		3_prime_UTR	Exon 19 of 19	ENSP00000407692.1

Frequencies

GnomAD3 genomes AF: 0.931 AC: 141355 AN: 151888 Hom.: 66297 Cov.: 30

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.971

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.983

Gnomad OTH AF: 0.939

GnomAD2 exomes AF: 0.965 AC: 241673 AN: 250502 AF XY: 0.966

Gnomad AFR exome AF: 0.800

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: 1427445 AN: 1461810 Hom.: 697720 Cov.: 77 AF XY: 0.976 AC XY: 709945 AN XY: 727210

African (AFR) AF: 0.797 AC: 26685 AN: 33468

American (AMR) AF: 0.983 AC: 43951 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 26032 AN: 26128

East Asian (EAS) AF: 0.957 AC: 37976 AN: 39696

South Asian (SAS) AF: 0.941 AC: 81179 AN: 86254

European-Finnish (FIN) AF: 0.996 AC: 53193 AN: 53420

Middle Eastern (MID) AF: 0.969 AC: 5587 AN: 5768

European-Non Finnish (NFE) AF: 0.984 AC: 1094291 AN: 1111972

Other (OTH) AF: 0.970 AC: 58551 AN: 60390

GnomAD4 genome AF: 0.931 AC: 141465 AN: 152006 Hom.: 66349 Cov.: 30 AF XY: 0.933 AC XY: 69301 AN XY: 74302

African (AFR) AF: 0.803 AC: 33215 AN: 41352

American (AMR) AF: 0.971 AC: 14843 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3449 AN: 3464

East Asian (EAS) AF: 0.943 AC: 4857 AN: 5148

South Asian (SAS) AF: 0.933 AC: 4491 AN: 4814

European-Finnish (FIN) AF: 0.997 AC: 10588 AN: 10618

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.983 AC: 66844 AN: 68002

Other (OTH) AF: 0.940 AC: 1983 AN: 2110

Alfa AF: 0.977 Hom.: 54269

Bravo AF: 0.923

TwinsUK AF: 0.987 AC: 3658

ALSPAC AF: 0.985 AC: 3795

ESP6500AA AF: 0.809 AC: 3564

ESP6500EA AF: 0.982 AC: 8442

ExAC AF: 0.960 AC: 116530

Asia WGS AF: 0.931 AC: 3237 AN: 3478

EpiCase AF: 0.983

EpiControl AF: 0.985

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 28, 2022

GeneDx

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

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.

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.97
DANN	Benign	0.29
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.095	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.019
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.028
Sift	Benign	0.74	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.025
MutPred		0.36		Loss of phosphorylation at T998 (P = 0.0717)
MPC		0.26
ClinPred		0.00051	T
GERP RS		-1.8
Varity_R		0.023
gMVP		0.11
Mutation Taster		=100/0	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: rs893253; hg19: chr2-209190528; COSMIC: COSV104578621;