chr2-208325795-A-T

Variant names:

• chr2-208325795-A-T
• rs893254
• NM_015040.4:c.2984A>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.2984A>T​(p.Gln995Leu) 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 1,613,742 control chromosomes in the GnomAD database, including 763,631 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66252 hom., cov: 31)
  • Exomes 𝑓: 0.98 (697379 hom.)
• Consequence: PIKFYVE NM_015040.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.44
• Publications: 30 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=1.1307615E-6).
• BP6: Variant 2-208325795-A-T is Benign according to our data. Variant chr2-208325795-A-T is described in ClinVar as Benign. ClinVar VariationId is 333909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.977 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.2984A>T	p.Gln995Leu	missense	Exon 20 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.2984A>T	p.Gln995Leu	missense	Exon 20 of 42	ENSP00000264380.4	Q9Y2I7-1
	PIKFYVE	ENST00000443896.5	TSL:1	n.*2335A>T		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407692.1	F8WEZ0
	PIKFYVE	ENST00000443896.5	TSL:1	n.*2335A>T		3_prime_UTR	Exon 19 of 19	ENSP00000407692.1	F8WEZ0

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141237 AN: 151878 Hom.: 66200 Cov.: 31

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.970

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.983

Gnomad OTH AF: 0.939

GnomAD2 exomes AF: 0.964 AC: 241668 AN: 250574 AF XY: 0.966

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 FIN exome AF: 0.997

Gnomad NFE exome AF: 0.983

Gnomad OTH exome AF: 0.978

GnomAD4 exome AF: 0.976 AC: 1427050 AN: 1461746 Hom.: 697379 Cov.: 78 AF XY: 0.976 AC XY: 709734 AN XY: 727164

African (AFR) AF: 0.796 AC: 26621 AN: 33464

American (AMR) AF: 0.982 AC: 43927 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 26026 AN: 26122

East Asian (EAS) AF: 0.957 AC: 37976 AN: 39696

South Asian (SAS) AF: 0.941 AC: 81162 AN: 86246

European-Finnish (FIN) AF: 0.996 AC: 53190 AN: 53418

Middle Eastern (MID) AF: 0.964 AC: 5559 AN: 5766

European-Non Finnish (NFE) AF: 0.984 AC: 1094072 AN: 1111934

Other (OTH) AF: 0.969 AC: 58517 AN: 60388

GnomAD4 genome AF: 0.930 AC: 141347 AN: 151996 Hom.: 66252 Cov.: 31 AF XY: 0.932 AC XY: 69244 AN XY: 74298

African (AFR) AF: 0.801 AC: 33131 AN: 41346

American (AMR) AF: 0.970 AC: 14832 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3449 AN: 3464

East Asian (EAS) AF: 0.943 AC: 4859 AN: 5150

South Asian (SAS) AF: 0.933 AC: 4492 AN: 4816

European-Finnish (FIN) AF: 0.997 AC: 10580 AN: 10610

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

European-Non Finnish (NFE) AF: 0.983 AC: 66827 AN: 68000

Other (OTH) AF: 0.940 AC: 1983 AN: 2110

Alfa AF: 0.977 Hom.: 54249

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: 116496

Asia WGS AF: 0.930 AC: 3235 AN: 3478

EpiCase AF: 0.983

EpiControl AF: 0.984

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Fleck corneal dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.040
Sift	Benign	0.096	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.28
ClinPred		0.0086	T
GERP RS		4.2
Varity_R		0.085
gMVP		0.22
Mutation Taster		=90/10	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: rs893254; hg19: chr2-209190519; COSMIC: COSV104578620;