rs28730674

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005026.5(PIK3CD):c.1366A>G(p.Thr456Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,142 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T456M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 11 hom., cov: 31)

Exomes 𝑓: 0.0031 ( 87 hom. )

Consequence

PIK3CD
NM_005026.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.02

Publications

15 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007569164).

BP6

Variant 1-9720138-A-G is Benign according to our data. Variant chr1-9720138-A-G is described in ClinVar as Benign. ClinVar VariationId is 474023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00392 (596/152234) while in subpopulation EAS AF = 0.0424 (219/5164). AF 95% confidence interval is 0.0378. There are 11 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CD	NM_005026.5 link	c.1366A>G	p.Thr456Ala	missense_variant	Exon 11 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.1366A>G	p.Thr456Ala	missense_variant	Exon 11 of 24	1	NM_005026.5	ENSP00000366563.4		O00329-1

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

596

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.0423

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.0222

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00762

AC:

1912

AN:

250772

AF XY:

0.00699

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.0378

Gnomad FIN exome

AF:

0.0213

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00604

GnomAD4 exome

AF:

0.00315

AC:

4601

AN:

1460908

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

2302

AN XY:

726774

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.0118

AC:

529

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

26136

East Asian (EAS)

AF:

0.0477

AC:

1894

AN:

39700

South Asian (SAS)

AF:

0.00385

AC:

332

AN:

86258

European-Finnish (FIN)

AF:

0.0210

AC:

1101

AN:

52462

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000430

AC:

478

AN:

1112000

Other (OTH)

AF:

0.00369

AC:

223

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

302

605

907

1210

1512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00392

AC:

596

AN:

152234

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

361

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41552

American (AMR)

AF:

0.00385

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.0424

AC:

219

AN:

5164

South Asian (SAS)

AF:

0.00456

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0222

AC:

236

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

67992

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.00351

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00705

AC:

856

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 24, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

PIK3CD-related disorder

Benign:1

Mar 22, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Immunodeficiency 14

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.8

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0041

.;T;T;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.45

.;T;T;T;.

MetaRNN

Benign

0.0076

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

.;.;N;.;.

PhyloP100

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.50

N;.;N;.;N

REVEL

Benign

0.13

Sift

Benign

0.26

T;.;T;.;T

Sift4G

Benign

0.080

T;T;T;T;T

Polyphen

0.0

B;.;B;B;.

Vest4

0.26

MVP

0.67

MPC

0.92

ClinPred

0.0085

GERP RS

-0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.054

gMVP

0.65

Mutation Taster

=94/6

polymorphism

(source)

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

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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