2-208326358-C-A

Position:

• chr2-208326358-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 13/20 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

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIKFYVE. . Gene score misZ 2.0469 (greater than the threshold 3.09). Trascript score misZ 3.5403 (greater than threshold 3.09). GenCC has associacion of gene with fleck corneal dystrophy.
• 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 id is 333917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208326358-C-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
PIKFYVE	NM_015040.4	c.3547C>A	p.Gln1183Lys	missense_variant	20/42	ENST00000264380.9	NP_055855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIKFYVE	ENST00000264380.9	c.3547C>A	p.Gln1183Lys	missense_variant	20/42	1	NM_015040.4	ENSP00000264380	P1
PIKFYVE	ENST00000452564.1	c.3379C>A	p.Gln1127Lys	missense_variant	19/25	2		ENSP00000405736

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

GnomAD3 exomes AF: 0.964 AC: 241498 AN: 250408 Hom.: 116777 AF XY: 0.966 AC XY: 130723 AN XY: 135284

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

Gnomad4 AFR exome AF: 0.795

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

Gnomad4 AFR AF: 0.802

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: 0.941

Alfa AF: 0.970 Hom.: 120128

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fleck corneal dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

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;.
MutationTaster	Benign	1.0	P
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

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: rs1529979; hg19: chr2-209191082;