rs397518423

chr1-9726972-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_005026.5(PIK3CD):c.3061G>A(p.Glu1021Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 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, 3 uncertain in NM_005026.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PIK3CD
• 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/exons	MANE	UniProt
PIK3CD	NM_005026.5	c.3061G>A	p.Glu1021Lys	missense_variant	24/24	ENST00000377346.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CD	ENST00000377346.9	c.3061G>A	p.Glu1021Lys	missense_variant	24/24	1	NM_005026.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727168

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 14 Pathogenic:13

Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Nov 30, 2017	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. -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	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 δ 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). 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 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Nov 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 11, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 strong, PP2 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	May 20, 2020	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. -
Pathogenic, no assertion criteria provided	research	Department of Medicine, University of Cambridge	Sep 10, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Mar 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 11, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Dec 20, 2020	- -

not provided Pathogenic:11

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	PIK3CD: PP1:Strong, PM2, PS4:Moderate, PM5:Supporting, PP2, PP3, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 30, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 01, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 08, 2021

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. -

Inherited Immunodeficiency Diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
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	D
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

Other links and lift over

dbSNP: rs397518423; hg19: chr1-9787030; COSMIC: COSV63126880; COSMIC: COSV63126880;