rs61755420

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.935C>G(p.Ser312Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,613,884 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S312S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 45 hom., cov: 32)

Exomes 𝑓: 0.027 ( 615 hom. )

Consequence

PIK3CD
NM_005026.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.09

Publications

23 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=0.0024999976).

BP6

Variant 1-9717541-C-G is Benign according to our data. Variant chr1-9717541-C-G is described in ClinVar as Benign. ClinVar VariationId is 440066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0187 (2851/152378) while in subpopulation NFE AF = 0.027 (1834/68042). AF 95% confidence interval is 0.0259. There are 45 homozygotes in GnomAd4. There are 1338 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 45 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CD	NM_005026.5 link	c.935C>G	p.Ser312Cys	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
PIK3CD	ENST00000377346.9 link	c.935C>G	p.Ser312Cys	missense_variant	Exon 8 of 24	1	NM_005026.5	ENSP00000366563.4		O00329-1

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2853

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00509

Gnomad AMI

AF:

0.0736

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.0496

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0238

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0270

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0202

AC:

5055

AN:

250332

AF XY:

0.0203

show subpopulations

Gnomad AFR exome

AF:

0.00364

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0476

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0263

Gnomad NFE exome

AF:

0.0296

Gnomad OTH exome

AF:

0.0248

GnomAD4 exome

AF:

0.0270

AC:

39495

AN:

1461506

Hom.:

615

Cov.:

AF XY:

0.0262

AC XY:

19068

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.00391

AC:

131

AN:

33476

American (AMR)

AF:

0.0119

AC:

533

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0467

AC:

1220

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00270

AC:

233

AN:

86256

European-Finnish (FIN)

AF:

0.0283

AC:

1507

AN:

53270

Middle Eastern (MID)

AF:

0.0175

AC:

101

AN:

5768

European-Non Finnish (NFE)

AF:

0.0307

AC:

34132

AN:

1111800

Other (OTH)

AF:

0.0271

AC:

1637

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

1975

3950

5924

7899

9874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1270

2540

3810

5080

6350

<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:

0.0187

AC:

2851

AN:

152378

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1338

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00507

AC:

211

AN:

41600

American (AMR)

AF:

0.0155

AC:

237

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0496

AC:

172

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00186

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0238

AC:

253

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0270

AC:

1834

AN:

68042

Other (OTH)

AF:

0.0298

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

148

295

443

590

738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0281

Hom.:

Bravo

AF:

0.0196

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0299

AC:

257

ExAC

AF:

0.0207

AC:

2509

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0295

EpiControl

AF:

0.0313

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIK3CD: BP4, BS1, BS2 -

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

0.063

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.055

.;T;D;.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.33

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.054

.;T;T;T;.

MetaRNN

Benign

0.0025

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;.;L;.;.

PhyloP100

2.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.6

D;.;N;.;D

REVEL

Benign

0.12

Sift

Benign

0.042

D;.;D;.;D

Sift4G

Uncertain

0.029

D;D;D;D;D

Polyphen

0.0

B;.;P;B;.

Vest4

0.12

MPC

1.6

ClinPred

0.023

GERP RS

3.6

Varity_R

0.21

gMVP

0.55

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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