Genetic Variant PIK3CD:c.931-9G>C (chr1-9717528-G-C) – ACMG Classification: Benign (-20 pts)

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.931-9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,613,626 control chromosomes in the GnomAD database, including 497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 24 hom., cov: 32)

Exomes 𝑓: 0.023 ( 473 hom. )

Consequence

PIK3CD
NM_005026.5 intron

Scores

Splicing: ADA: 0.00002334

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0980

Publications

3 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
immunodeficiency 14b, autosomal recessive
Inheritance: Unknown, AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
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 (BayesDel_noAF=-0.82).

BP6

Variant 1-9717528-G-C is Benign according to our data. Variant chr1-9717528-G-C is described in ClinVar as Benign. ClinVar VariationId is 440067.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 = 0.0169 (2575/152294) while in subpopulation NFE AF = 0.0248 (1686/68018). AF 95% confidence interval is 0.0238. There are 24 homozygotes in GnomAd4. There are 1223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005026.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIK3CD	NM_005026.5	MANE Select	c.931-9G>C	intron	N/A	NP_005017.3
PIK3CD	NM_001437546.1		c.931-9G>C	intron	N/A	NP_001424475.1	A0A2K8FKV1
PIK3CD	NM_001350234.2		c.931-9G>C	intron	N/A	NP_001337163.1	B7ZM44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.931-9G>C	intron	N/A	ENSP00000366563.4	O00329-1
PIK3CD	ENST00000361110.6	TSL:1	c.826-9G>C	intron	N/A	ENSP00000354410.2	F8W9P4
PIK3CD	ENST00000892288.1		c.931-9G>C	intron	N/A	ENSP00000562347.1

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2575

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0231

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0248

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0170

AC:

4255

AN:

249950

AF XY:

0.0166

show subpopulations

Gnomad AFR exome

AF:

0.00469

Gnomad AMR exome

AF:

0.0181

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0268

Gnomad NFE exome

AF:

0.0237

Gnomad OTH exome

AF:

0.0209

GnomAD4 exome

AF:

0.0227

AC:

33118

AN:

1461332

Hom.:

473

Cov.:

AF XY:

0.0218

AC XY:

15821

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.00353

AC:

118

AN:

33472

American (AMR)

AF:

0.0177

AC:

793

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0168

AC:

439

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000487

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0258

AC:

1373

AN:

53224

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0262

AC:

29118

AN:

1111704

Other (OTH)

AF:

0.0202

AC:

1219

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1596

3191

4787

6382

7978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1114

2228

3342

4456

5570

<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:

0.0169

AC:

2575

AN:

152294

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1223

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00447

AC:

186

AN:

41570

American (AMR)

AF:

0.0226

AC:

345

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0231

AC:

245

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0248

AC:

1686

AN:

68018

Other (OTH)

AF:

0.0175

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0207

Hom.:

Bravo

AF:

0.0167

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0229

EpiControl

AF:

0.0231

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Immunodeficiency 14 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.3

(source)

DANN

Benign

0.59

PhyloP100

-0.098

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over