rs28730670

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1PM2PP3_ModeratePP5_Moderate

The NM_005026.5(PIK3CD):​c.1002C>A​(p.Asn334Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N334N) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3CD
NM_005026.5 missense

Scores

5
8
6

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: -0.927
Variant links:
Genes affected
PIK3CD (HGNC:8977): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta) Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I PI3K found primarily in leukocytes. Like other class I PI3Ks (p110-alpha p110-beta, and p110-gamma), the encoded protein binds p85 adapter proteins and GTP-bound RAS. However, unlike the other class I PI3Ks, this protein phosphorylates itself, not p85 protein.[provided by RefSeq, Jul 2010]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1
Transcript NM_005026.5 (PIK3CD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 578525
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.852
PP5
Variant 1-9717608-C-A is Pathogenic according to our data. Variant chr1-9717608-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132806.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIK3CDNM_005026.5 linkc.1002C>A p.Asn334Lys missense_variant Exon 8 of 24 ENST00000377346.9 NP_005017.3 O00329-1A0A2K8FKV1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PIK3CDENST00000377346.9 linkc.1002C>A p.Asn334Lys missense_variant Exon 8 of 24 1 NM_005026.5 ENSP00000366563.4 O00329-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000136
Hom.:
0

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Immunodeficiency 14 Pathogenic:2
Feb 24, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 132806). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects PIK3CD function (PMID: 24165795, 28167755). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIK3CD protein function. This missense change has been observed in individual(s) with clinical features of activated PIK3 delta syndrome (PMID: 24165795; Invitae; external communication). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 334 of the PIK3CD protein (p.Asn334Lys). -

Jan 01, 2014
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Benign
-0.076
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.091
.;T;D;.;T
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.76
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
.;D;D;D;.
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Uncertain
2.9
.;.;M;.;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-5.5
D;.;D;.;D
REVEL
Uncertain
0.44
Sift
Uncertain
0.0020
D;.;D;.;D
Sift4G
Uncertain
0.0040
D;D;D;D;D
Polyphen
1.0
D;.;D;D;.
Vest4
0.77
MutPred
0.40
Gain of methylation at N299 (P = 0.0143);Gain of methylation at N299 (P = 0.0143);.;Gain of methylation at N299 (P = 0.0143);Gain of methylation at N299 (P = 0.0143);
MVP
0.88
MPC
1.7
ClinPred
1.0
D
GERP RS
-7.4
Varity_R
0.93
gMVP
0.88

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28730670; hg19: chr1-9777666; COSMIC: COSV63128871; COSMIC: COSV63128871; API