18-41957721-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002647.4(PIK3C3):ā€‹c.220G>Cā€‹(p.Val74Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PIK3C3
NM_002647.4 missense

Scores

1
13
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.52
Variant links:
Genes affected
PIK3C3 (HGNC:8974): (phosphatidylinositol 3-kinase catalytic subunit type 3) Enables 1-phosphatidylinositol-3-kinase activity. Involved in early endosome to late endosome transport and regulation of cytokinesis. Acts upstream of or within autophagy and protein lipidation. Located in autolysosome; late endosome; and midbody. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PIK3C3NM_002647.4 linkuse as main transcriptc.220G>C p.Val74Leu missense_variant 2/25 ENST00000262039.9 NP_002638.2 Q8NEB9
PIK3C3XM_047437549.1 linkuse as main transcriptc.220G>C p.Val74Leu missense_variant 2/22 XP_047293505.1
PIK3C3XM_047437551.1 linkuse as main transcriptc.220G>C p.Val74Leu missense_variant 2/14 XP_047293507.1
PIK3C3NM_001308020.2 linkuse as main transcriptc.68+2362G>C intron_variant NP_001294949.1 A8MYT4B4DPV9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PIK3C3ENST00000262039.9 linkuse as main transcriptc.220G>C p.Val74Leu missense_variant 2/251 NM_002647.4 ENSP00000262039.3 Q8NEB9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000137
AC:
2
AN:
1461082
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726880
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000450
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 29, 2022The c.220G>C (p.V74L) alteration is located in exon 2 (coding exon 2) of the PIK3C3 gene. This alteration results from a G to C substitution at nucleotide position 220, causing the valine (V) at amino acid position 74 to be replaced by a leucine (L). 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
0.42
BayesDel_addAF
Uncertain
0.065
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Uncertain
0.093
D
MetaRNN
Uncertain
0.71
D;D;D
MetaSVM
Uncertain
0.092
D
MutationAssessor
Uncertain
2.0
M;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-2.0
N;.;.
REVEL
Uncertain
0.59
Sift
Benign
0.045
D;.;.
Sift4G
Benign
0.13
T;.;T
Polyphen
0.87
P;.;.
Vest4
0.53
MutPred
0.68
Loss of MoRF binding (P = 0.0963);Loss of MoRF binding (P = 0.0963);Loss of MoRF binding (P = 0.0963);
MVP
0.78
MPC
0.36
ClinPred
0.95
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.35
gMVP
0.50

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-39537686; API