rs10932258

Variant names:

• chr2-208320256-G-A
• rs10932258
• NM_015040.4:c.2087G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-208320256-G-A
• chr2-208320256-G-C
• chr2-208320256-G-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.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. 14/21 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:4
• Conservation: PhyloP100: 7.52
• Publications: 28 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 333897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIKFYVE	NM_015040.4	MANE Select	c.2087G>A	p.Ser696Asn	missense	Exon 17 of 42	NP_055855.2	Q9Y2I7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIKFYVE	ENST00000264380.9	TSL:1 MANE Select	c.2087G>A	p.Ser696Asn	missense	Exon 17 of 42	ENSP00000264380.4	Q9Y2I7-1
	PIKFYVE	ENST00000443896.5	TSL:1	n.*1438G>A		non_coding_transcript_exon	Exon 16 of 19	ENSP00000407692.1	F8WEZ0
	PIKFYVE	ENST00000443896.5	TSL:1	n.*1438G>A		3_prime_UTR	Exon 16 of 19	ENSP00000407692.1	F8WEZ0

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

GnomAD2 exomes AF: 0.998 AC: 249202 AN: 249662 AF XY: 0.999

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 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

African (AFR) AF: 0.975 AC: 32547 AN: 33372

American (AMR) AF: 0.998 AC: 44451 AN: 44520

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26037 AN: 26038

East Asian (EAS) AF: 1.00 AC: 39452 AN: 39452

South Asian (SAS) AF: 1.00 AC: 85709 AN: 85718

European-Finnish (FIN) AF: 1.00 AC: 53348 AN: 53350

Middle Eastern (MID) AF: 0.998 AC: 5657 AN: 5668

European-Non Finnish (NFE) AF: 1.00 AC: 1110092 AN: 1110140

Other (OTH) AF: 0.998 AC: 60145 AN: 60244

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

African (AFR) AF: 0.976 AC: 40596 AN: 41576

American (AMR) AF: 0.997 AC: 15251 AN: 15296

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10621 AN: 10622

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68026 AN: 68034

Other (OTH) AF: 0.997 AC: 2107 AN: 2114

Alfa AF: 0.998 Hom.: 63818

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fleck corneal dystrophy (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	N
PhyloP100		7.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.29
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.27
ClinPred		0.022	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.18
Mutation Taster		=92/8	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: rs10932258; hg19: chr2-209184980; COSMIC: COSV52246259;