rs10932258

chr2-208320256-G-Achr2-208320256-G-Cchr2-208320256-G-T

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.2087G>A(p.Ser696Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,610,828 control chromosomes in the GnomAD database, including 803,335 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 0.99 (75137 hom., cov: 32)
  • Exomes 𝑓: 1.0 (728198 hom.)
• Consequence: PIKFYVE NM_015040.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.52

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 where missense usually causes diseases, PIKFYVE
• BP4: Computational evidence support a benign effect (MetaRNN=5.648329E-7).
• BP6: Variant 2-208320256-G-A is Benign according to our data. Variant chr2-208320256-G-A is described in ClinVar as [Benign]. Clinvar id is 333897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208320256-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIKFYVE	NM_015040.4	c.2087G>A	p.Ser696Asn	missense_variant	17/42	ENST00000264380.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIKFYVE	ENST00000264380.9	c.2087G>A	p.Ser696Asn	missense_variant	17/42	1	NM_015040.4	P1
PIKFYVE	ENST00000443896.5	c.*1438G>A		3_prime_UTR_variant, NMD_transcript_variant	16/19	1
PIKFYVE	ENST00000452564.1	c.1919G>A	p.Ser640Asn	missense_variant	16/25	2

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151171 AN: 152208 Hom.: 75082 Cov.: 32

Gnomad AFR AF: 0.976

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.997

GnomAD3 exomes AF: 0.998 AC: 249202 AN: 249662 Hom.: 124376 AF XY: 0.999 AC XY: 134792 AN XY: 134972

Gnomad AFR exome AF: 0.975

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1457438 AN: 1458502 Hom.: 728198 Cov.: 48 AF XY: 0.999 AC XY: 725074 AN XY: 725522

Gnomad4 AFR exome AF: 0.975

Gnomad4 AMR exome AF: 0.998

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome AF: 0.993 AC: 151285 AN: 152326 Hom.: 75137 Cov.: 32 AF XY: 0.994 AC XY: 74009 AN XY: 74480

Gnomad4 AFR AF: 0.976

Gnomad4 AMR AF: 0.997

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.997

Alfa AF: 0.998 Hom.: 63145

Bravo AF: 0.992

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.977 AC: 4305

ESP6500EA AF: 1.00 AC: 8589

ExAC AF: 0.998 AC: 121099

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fleck corneal dystrophy Benign:2

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	17
Dann	Benign	0.21
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	5.6e-7	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.65	N;N
REVEL	Benign	0.29
Sift	Benign	1.0	T;T
Sift4G	Benign	0.86	T;T
Polyphen		0.0	B;B
Vest4		0.039
MPC		0.27
ClinPred		0.022	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.18

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: rs10932258; hg19: chr2-209184980; COSMIC: COSV52246259;