rs143068130

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005026.5(PIK3CD):c.1777G>C(p.Gly593Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00024 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

PIK3CD
NM_005026.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1

Conservation

PhyloP100: 5.23

Publications

18 publications found

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]

PIK3CD Gene-Disease associations (from GenCC):

immunodeficiency 14
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
immunodeficiency 14b, autosomal recessive
Inheritance: AR, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
activated PI3K-delta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIK3CD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.05640745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CD	NM_005026.5 link	c.1777G>C	p.Gly593Arg	missense_variant	Exon 14 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.1777G>C	p.Gly593Arg	missense_variant	Exon 14 of 24	1	NM_005026.5	ENSP00000366563.4		O00329-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000123

AC:

AN:

251102

AF XY:

0.0000957

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000245

AC:

358

AN:

1461144

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

726926

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000247

AC:

AN:

52736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000299

AC:

332

AN:

1111974

Other (OTH)

AF:

0.000132

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000197

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41456

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1777G>C variant in the PIK3CD gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1777G>C variant is observed in 11/65934 (0.02%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). In silico splice prediction models predict that c.1777G>C may create a cryptic splice donor site in exon 14, however this variant is not predicted to affect the natural splice donor site. In the absence of RNA/functional studies, the actual effect of the c.1777G>C change in this individual is unknown. If c.1777G>C does not alter splicing, it will result in the G593R missense change. The G593R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret c.1777G>C as a variant of uncertain significance. -

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

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Immunodeficiency 14

Uncertain:1

Nov 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 593 of the PIK3CD protein (p.Gly593Arg). This variant is present in population databases (rs143068130, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PIK3CD-related conditions. ClinVar contains an entry for this variant (Variation ID: 424409). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Activated PI3K-delta syndrome

Benign:1

Rarefied Biosciences Lab

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

p.Gly593Arg is classified here as likely benign due to experimental evidence showing no gain of mTOR function in B or T cells. The proportion of transitional B cells is normal. The proportion of circulating TFH is normal. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.28

.;T;T;.;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

.;D;D;D;.

M_CAP

Benign

0.040

MetaRNN

Benign

0.056

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-2.0

.;.;N;.;.

PhyloP100

5.2

PrimateAI

Uncertain

0.68

PROVEAN

Benign

3.3

N;.;N;.;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.17

B;.;B;B;.

Vest4

0.31

MVP

0.15

MPC

1.3

ClinPred

0.088

GERP RS

5.2

Varity_R

0.29

gMVP

0.58

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs143068130

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over