2-208325606-T-C

Variant names:

• chr2-208325606-T-C
• rs2363468
• NM_015040.4:c.2795T>C

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.2795T>C​(p.Leu932Ser) 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 1,614,034 control chromosomes in the GnomAD database, including 763,520 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L932L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.93 (66322 hom., cov: 31)
  • Exomes 𝑓: 0.98 (697198 hom.)
• Consequence: PIKFYVE NM_015040.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.880
• Publications: 35 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=9.157526E-7).
• BP6: Variant 2-208325606-T-C is Benign according to our data. Variant chr2-208325606-T-C is described in ClinVar as Benign. ClinVar VariationId is 333905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 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.2795T>C	p.Leu932Ser	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.2795T>C	p.Leu932Ser	missense	Exon 20 of 42	ENSP00000264380.4
	PIKFYVE	ENST00000443896.5	TSL:1	n.*2146T>C		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407692.1
	PIKFYVE	ENST00000443896.5	TSL:1	n.*2146T>C		3_prime_UTR	Exon 19 of 19	ENSP00000407692.1

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141402 AN: 152064 Hom.: 66270 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: 0.931

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.939

GnomAD2 exomes AF: 0.964 AC: 242074 AN: 251044 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: 0.996

Gnomad NFE exome AF: 0.983

Gnomad OTH exome AF: 0.977

GnomAD4 exome AF: 0.976 AC: 1426917 AN: 1461852 Hom.: 697198 Cov.: 80 AF XY: 0.976 AC XY: 709669 AN XY: 727220

African (AFR) AF: 0.795 AC: 26627 AN: 33476

American (AMR) AF: 0.982 AC: 43922 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 26040 AN: 26136

East Asian (EAS) AF: 0.957 AC: 37980 AN: 39700

South Asian (SAS) AF: 0.941 AC: 81149 AN: 86254

European-Finnish (FIN) AF: 0.995 AC: 53153 AN: 53416

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

European-Non Finnish (NFE) AF: 0.984 AC: 1093974 AN: 1112000

Other (OTH) AF: 0.969 AC: 58511 AN: 60392

GnomAD4 genome AF: 0.930 AC: 141512 AN: 152182 Hom.: 66322 Cov.: 31 AF XY: 0.932 AC XY: 69350 AN XY: 74410

African (AFR) AF: 0.802 AC: 33275 AN: 41490

American (AMR) AF: 0.970 AC: 14824 AN: 15288

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

East Asian (EAS) AF: 0.944 AC: 4870 AN: 5158

South Asian (SAS) AF: 0.933 AC: 4493 AN: 4818

European-Finnish (FIN) AF: 0.997 AC: 10577 AN: 10610

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

European-Non Finnish (NFE) AF: 0.982 AC: 66835 AN: 68026

Other (OTH) AF: 0.940 AC: 1987 AN: 2114

Alfa AF: 0.968 Hom.: 276670

Bravo AF: 0.922

TwinsUK AF: 0.986 AC: 3657

ALSPAC AF: 0.984 AC: 3794

ESP6500AA AF: 0.807 AC: 3555

ESP6500EA AF: 0.982 AC: 8442

ExAC AF: 0.960 AC: 116495

EpiCase AF: 0.982

EpiControl AF: 0.985

ClinVar

ClinVar submissions as Germline

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	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Benign	0.47
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.0083	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.92	N
PhyloP100		0.88
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.069
Sift	Benign	1.0	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.39
ClinPred		0.00063	T
GERP RS		5.2
Varity_R		0.058
gMVP		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2363468; hg19: chr2-209190330; COSMIC: COSV104578605;