dbSNP rs397518423: PIK3CD:p.Glu1021Lys (chr1-9726972-G-A) – ACMG Classification: Pathogenic (12 pts)

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]

PIK3CD links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005026.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-9726972-G-A is Pathogenic according to our data. Variant chr1-9726972-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 88675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-9726972-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CD	NM_005026.5 link	c.3061G>A	p.Glu1021Lys	missense_variant	Exon 24 of 24	ENST00000377346.9	NP_005017.3	O00329-1A0A2K8FKV1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CD	ENST00000377346.9 link	c.3061G>A	p.Glu1021Lys	missense_variant	Exon 24 of 24	1	NM_005026.5	ENSP00000366563.4		O00329-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 14

Pathogenic:14

Dec 20, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2020

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIK3CD NM_005026.4 exon 24 p.Glu1021Lys (c.3061G>A): This variant has been well reported in the literature and has been identified in several individuals with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS), at least two of whom were reported as de novo. This variant has also been reported to segregate with disease in numerous affected family members (Selected publications: Jou 2006 PMID:16984281, Angulo 2013 PMID:24136356, Crank 2014 PMID:24610295, Lucas 2014 PMID:24165795, Hartman 2015 PMID:25352054, Elgizouli 2016 PMID:26437962, Cansever 2020 PMID:31033788). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:88675). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In vitro functional studies also predict that this variant will impact the protein affecting binding and resulting in a gain of function effect (Angulo 2013 PMID:24136356, Lucas 2014 PMID:24165795). In summary, this variant is classified as pathogenic. -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 16984281, 24136356, PM6_S) and co-segregated with Immunodeficiency 14A, autosomal dominant in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 24136356, 24165795). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.627>=0.6). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1021 of the PIK3CD protein (p.Glu1021Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with activated phosphoinositide 3-Kinase Œ¥ syndrome (APDS) (PMID: 16984281, 24136356, 24165795, 24610295, 25352054, 26437962). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88675). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PIK3CD protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PIK3CD function (PMID: 24136356, 24165795, 26732860). For these reasons, this variant has been classified as Pathogenic. -

Nov 30, 2017

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The observed variant c.3061G>A (p.E1021K) is not reported in 1000 genomes and ExAC databases. The in silico prediction of the variant is disease causing in MutationTaster2 and tolerated in SIFT. -

Mar 23, 2016

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 strong, PP2 supporting -

Apr 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 10, 2013

Department of Medicine, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 11, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nov 21, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Pathogenic, for Activated PI3K-delta syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1-Strong => PP1 upgraded in strength to Strong (PMID:24136356,24165795). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24136356). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Observed in multiple unrelated patients and absent from controls (PMID:16984281,24165795,24610295,24136356). PS3 => Well-established functional studies show a deleterious effect (PMID:24136356). -

not provided

Pathogenic:11

Jul 01, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 30, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CD c.3061G>A, p.Glu1021Lys variant (rs397518423) has been reported in multiple individuals with hypogammaglobulinemia (Jou 2006) or hyper-IgM syndrome (Angulo 2013, Crank 2014). This variant is reported as pathogenic in ClinVar (Variation ID: 88675) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.627). However, in vitro and in vivo functional assays demonstrate the variant to be a gain of function, with enhanced membrane association, PIP3 production and PI3K pathway activation (Angulo 2013, Lucas 2014). Based on available information, this variant is considered to be pathogenic. References: Angulo I et al.: Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science 2013; 342(6160):866-871. PMID: 24136356. Crank M et al.: Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J Clin Immunol. 2014; 34(3):272-276. PMID: 24610295. Jou S et al.: Identification of variations in the human phosphoinositide 3-kinase p110delta gene in children with primary B-cell immunodeficiency of unknown aetiology. Int J Immunogenet. 2006; 33(5):361-369. PMID: 16984281. Lucas C et al.: Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014; 15(1):88-97. PMID: 24165795. -

Dec 08, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant enhances membrane association and kinase activity of the PIK3CD protein, consistent with a gain-of-function effect (Angulo et al., 2013; Avery et al., 2018).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24698326, 25352054, 26437962, 31760094, 27555459, 31033788, 31045771, 24610295, 24165795, 16984281, 26732860, 24136356, 27980538, 27596086, 28167755, 28601916, 29200144, 28469999, 29077208, 28072954, 27426521, 28104464, 30018075, 28842185, 29107464, 30499059, 30738173, 32265996, 31953711, 30919572, 32499645, 32581362, 33995405, 34060650, 33080915, 32349894, 33225392, 33144682, 32758532, 32888943, 32901917, 28252636, 34134972, 32531373, 33942430, 33726816) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIK3CD: PP1:Strong, PM2, PS4:Moderate, PM5:Supporting, PP2, PP3, PS3:Supporting -

Inborn genetic diseases

Pathogenic:1

Dec 21, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3061G>A (p.E1021K) alteration is located in exon 24 (coding exon 22) of the PIK3CD gene. This alteration results from a G to A substitution at nucleotide position 3061, causing the glutamic acid (E) at amino acid position 1021 to be replaced by a lysine (K)._x000D_ _x000D_ for autosomal dominant PIK3CD-related immunodeficiency; however, its clinical significance for autosomal recessive PIK3CD-related immunodeficiency is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals and confirmed de novo in multiple individuals with clinical features consistent with autosomal dominant PIK3CD-related immunodeficiency (Angulo, 2013; Lucas, 2014; Crank, 2014; Li, 2019; Lu, 2021; Craig, 2022). This amino acid position is highly conserved in available vertebrate species. Functional studies have been performed that suggest this variant alters protein function (Angulo, 2013; Lucas, 2014). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Combined immunodeficiency with faciooculoskeletal anomalies;C3714976:Immunodeficiency 14;C5543301:Immunodeficiency 14b, autosomal recessive

Pathogenic:1

Dec 08, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inherited Immunodeficiency Diseases

Pathogenic:1

Jan 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

.;T;D;.;T

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

.;D;D;D;.

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.9

.;.;L;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.5

D;.;D;.;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

D;.;D;.;D

Sift4G

Benign

0.078

T;T;T;T;T

Polyphen

1.0

D;.;D;D;.

Vest4

0.54

MutPred

0.46

Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);.;Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);

MVP

0.88

MPC

2.2

ClinPred

0.99

GERP RS

3.7

Varity_R

0.90

gMVP

0.95

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.

rs397518423

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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