2-208325908-T-G

Position:

• chr2-208325908-T-G

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.3097T>G​(p.Ser1033Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,612,464 control chromosomes in the GnomAD database, including 15,306 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 0.13 (1411 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13895 hom.)
• Consequence: PIKFYVE NM_015040.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.81

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 (HGNC:):

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=0.001552254).
• BP6: Variant 2-208325908-T-G is Benign according to our data. Variant chr2-208325908-T-G is described in ClinVar as [Benign]. Clinvar id is 333911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIKFYVE	NM_015040.4	c.3097T>G	p.Ser1033Ala	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.3097T>G	p.Ser1033Ala	missense_variant	20/42	1	NM_015040.4	ENSP00000264380.4
PIKFYVE	ENST00000443896.5	n.*2448T>G		non_coding_transcript_exon_variant	19/19	1		ENSP00000407692.1
PIKFYVE	ENST00000443896.5	n.*2448T>G		3_prime_UTR_variant	19/19	1		ENSP00000407692.1
PIKFYVE	ENST00000452564.1	c.2929T>G	p.Ser977Ala	missense_variant	19/25	2		ENSP00000405736.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20063 AN: 152068 Hom.: 1412 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.117 AC: 29323 AN: 251002 Hom.: 1917 AF XY: 0.119 AC XY: 16170 AN XY: 135640

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0821

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.00701

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.0985

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.134 AC: 196232 AN: 1460276 Hom.: 13895 Cov.: 74 AF XY: 0.134 AC XY: 97656 AN XY: 726524

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.0862

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.0121

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.132 AC: 20064 AN: 152188 Hom.: 1411 Cov.: 32 AF XY: 0.128 AC XY: 9544 AN XY: 74404

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.0126

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.0985

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.129

Alfa AF: 0.137 Hom.: 3644

Bravo AF: 0.132

TwinsUK AF: 0.150 AC: 555

ALSPAC AF: 0.145 AC: 560

ESP6500AA AF: 0.143 AC: 629

ESP6500EA AF: 0.140 AC: 1207

ExAC AF: 0.120 AC: 14619

Asia WGS AF: 0.0790 AC: 277 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fleck corneal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.083
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.10
Sift	Benign	0.20	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.089	B;B
Vest4		0.049
MPC		0.27
ClinPred		0.013	T
GERP RS		-0.48
Varity_R		0.032
gMVP		0.30

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: rs999890; hg19: chr2-209190632; COSMIC: COSV52239127;