Genetic Variant PIK3CD:p.Asn334Asn (chr1-9717608-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005026.5(PIK3CD):c.1002C>T(p.Asn334Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,064 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 6 hom. )

Consequence

PIK3CD
NM_005026.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.927

Publications

49 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), Ambry Genetics, ClinGen
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 1-9717608-C-T is Benign according to our data. Variant chr1-9717608-C-T is described in ClinVar as Benign. ClinVar VariationId is 541092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.927 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00479 (730/152330) while in subpopulation AFR AF = 0.0164 (682/41586). AF 95% confidence interval is 0.0154. There are 12 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 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	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3CD	NM_005026.5	MANE Select	c.1002C>T	p.Asn334Asn	synonymous	Exon 8 of 24	NP_005017.3
PIK3CD	NM_001437546.1		c.1002C>T	p.Asn334Asn	synonymous	Exon 7 of 23	NP_001424475.1	A0A2K8FKV1
PIK3CD	NM_001350234.2		c.1002C>T	p.Asn334Asn	synonymous	Exon 8 of 24	NP_001337163.1	B7ZM44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.1002C>T	p.Asn334Asn	synonymous	Exon 8 of 24	ENSP00000366563.4	O00329-1
PIK3CD	ENST00000361110.6	TSL:1	c.897C>T	p.Asn299Asn	synonymous	Exon 7 of 23	ENSP00000354410.2	F8W9P4
PIK3CD	ENST00000892288.1		c.1002C>T	p.Asn334Asn	synonymous	Exon 8 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes

AF:

0.00478

AC:

728

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00136

AC:

341

AN:

250744

AF XY:

0.000832

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000629

AC:

919

AN:

1461734

Hom.:

Cov.:

AF XY:

0.000575

AC XY:

418

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0191

AC:

641

AN:

33476

American (AMR)

AF:

0.000984

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.000661

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000630

AC:

AN:

1111966

Other (OTH)

AF:

0.00152

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00479

AC:

730

AN:

152330

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0164

AC:

682

AN:

41586

American (AMR)

AF:

0.00163

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68028

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

106

141

176

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:

0.00199

Hom.:

Bravo

AF:

0.00540

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

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

-0.47

CADD

Benign

3.6

(source)

DANN

Benign

0.94

PhyloP100

-0.93

Mutation Taster

=97/3

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over