10-22541981-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005028.5(PIP4K2A):​c.859G>A​(p.Glu287Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,908 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 1 hom. )

Consequence

PIP4K2A
NM_005028.5 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Publications

1 publications found
Variant links:
Genes affected
PIP4K2A (HGNC:8997): (phosphatidylinositol-5-phosphate 4-kinase type 2 alpha) Phosphatidylinositol-5,4-bisphosphate, the precursor to second messengers of the phosphoinositide signal transduction pathways, is thought to be involved in the regulation of secretion, cell proliferation, differentiation, and motility. The protein encoded by this gene is one of a family of enzymes capable of catalyzing the phosphorylation of phosphatidylinositol-5-phosphate on the fourth hydroxyl of the myo-inositol ring to form phosphatidylinositol-5,4-bisphosphate. The amino acid sequence of this enzyme does not show homology to other kinases, but the recombinant protein does exhibit kinase activity. This gene is a member of the phosphatidylinositol-5-phosphate 4-kinase family. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIP4K2ANM_005028.5 linkc.859G>A p.Glu287Lys missense_variant Exon 8 of 10 ENST00000376573.9 NP_005019.2 P48426-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PIP4K2AENST00000376573.9 linkc.859G>A p.Glu287Lys missense_variant Exon 8 of 10 1 NM_005028.5 ENSP00000365757.4 P48426-1
PIP4K2AENST00000545335.5 linkc.682G>A p.Glu228Lys missense_variant Exon 8 of 10 2 ENSP00000442098.1 P48426-2
PIP4K2AENST00000323883.11 linkc.439G>A p.Glu147Lys missense_variant Exon 6 of 8 2 ENSP00000326294.7 H7BXS3
PIP4K2AENST00000604912.1 linkc.397G>A p.Glu133Lys missense_variant Exon 5 of 5 2 ENSP00000473858.1 S4R320

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000279
AC:
7
AN:
251178
AF XY:
0.0000295
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000239
AC:
35
AN:
1461778
Hom.:
1
Cov.:
33
AF XY:
0.0000275
AC XY:
20
AN XY:
727206
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000696
AC:
6
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000234
AC:
26
AN:
1111932
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74306
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41430
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.433
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 09, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.859G>A (p.E287K) alteration is located in exon 8 (coding exon 8) of the PIP4K2A gene. This alteration results from a G to A substitution at nucleotide position 859, causing the glutamic acid (E) at amino acid position 287 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Uncertain
0.078
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.22
T;.;.;T
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Uncertain
0.53
D;D;D;D
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.1
L;.;.;.
PhyloP100
7.6
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-3.1
D;D;D;.
REVEL
Uncertain
0.33
Sift
Benign
0.063
T;D;T;.
Sift4G
Benign
0.37
T;T;T;T
Polyphen
0.99
D;.;.;.
Vest4
0.88
MVP
0.53
MPC
0.50
ClinPred
0.29
T
GERP RS
6.1
Varity_R
0.85
gMVP
0.56
Mutation Taster
=35/65
disease causing

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

Other links and lift over

dbSNP: rs527968606; hg19: chr10-22830910; API