rs1529979

Variant names:

• chr2-208326358-C-A
• rs1529979
• NM_015040.4:c.3547C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-208326358-C-A
• chr2-208326358-C-G
• chr2-208326358-C-T

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.3547C>A​(p.Gln1183Lys) variant causes a missense change. The variant allele was found at a frequency of 0.972 in 1,613,836 control chromosomes in the GnomAD database, including 763,665 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66385 hom., cov: 31)
  • Exomes 𝑓: 0.98 (697280 hom.)
• Consequence: PIKFYVE NM_015040.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.40
• Publications: 32 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=6.253979E-7).
• BP6: Variant 2-208326358-C-A is Benign according to our data. Variant chr2-208326358-C-A is described in ClinVar as Benign. ClinVar VariationId is 333917.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIKFYVE	NM_015040.4	c.3547C>A	p.Gln1183Lys	missense_variant	Exon 20 of 42	ENST00000264380.9	NP_055855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIKFYVE	ENST00000264380.9	c.3547C>A	p.Gln1183Lys	missense_variant	Exon 20 of 42	1	NM_015040.4	ENSP00000264380.4
PIKFYVE	ENST00000452564.1	c.3379C>A	p.Gln1127Lys	missense_variant	Exon 19 of 25	2		ENSP00000405736.1

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141514 AN: 152146 Hom.: 66333 Cov.: 31

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.970

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.983

Gnomad OTH AF: 0.940

GnomAD2 exomes AF: 0.964 AC: 241498 AN: 250408 AF XY: 0.966

Gnomad AFR exome AF: 0.799

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: 1426863 AN: 1461572 Hom.: 697280 Cov.: 62 AF XY: 0.976 AC XY: 709657 AN XY: 727096

African (AFR) AF: 0.795 AC: 26618 AN: 33464

American (AMR) AF: 0.982 AC: 43877 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 26024 AN: 26120

East Asian (EAS) AF: 0.957 AC: 37975 AN: 39696

South Asian (SAS) AF: 0.941 AC: 81081 AN: 86168

European-Finnish (FIN) AF: 0.996 AC: 53179 AN: 53406

Middle Eastern (MID) AF: 0.964 AC: 5561 AN: 5768

European-Non Finnish (NFE) AF: 0.984 AC: 1094034 AN: 1111904

Other (OTH) AF: 0.969 AC: 58514 AN: 60386

GnomAD4 genome AF: 0.930 AC: 141624 AN: 152264 Hom.: 66385 Cov.: 31 AF XY: 0.932 AC XY: 69410 AN XY: 74454

African (AFR) AF: 0.802 AC: 33301 AN: 41508

American (AMR) AF: 0.970 AC: 14836 AN: 15298

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

East Asian (EAS) AF: 0.944 AC: 4883 AN: 5174

South Asian (SAS) AF: 0.933 AC: 4502 AN: 4826

European-Finnish (FIN) AF: 0.997 AC: 10596 AN: 10626

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

European-Non Finnish (NFE) AF: 0.983 AC: 66870 AN: 68044

Other (OTH) AF: 0.941 AC: 1985 AN: 2110

Alfa AF: 0.966 Hom.: 177049

Bravo AF: 0.922

TwinsUK AF: 0.986 AC: 3657

ALSPAC AF: 0.984 AC: 3794

ESP6500AA AF: 0.807 AC: 3554

ESP6500EA AF: 0.982 AC: 8442

ExAC AF: 0.960 AC: 116510

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.16
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	6.3e-7	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.81	N;.
PhyloP100		4.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.055
Sift	Benign	1.0	T;T
Sift4G	Benign	0.97	T;T
Polyphen		0.0	B;B
Vest4		0.031
MPC		0.36
ClinPred		0.00077	T
GERP RS		4.7
Varity_R		0.058
gMVP		0.26
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: rs1529979; hg19: chr2-209191082; COSMIC: COSV104578606; COSMIC: COSV104578606;