rs139848768

Variant names:

• chr1-9722328-C-T
• rs139848768
• NM_005026.5:c.2319C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005026.5(PIK3CD):​c.2319C>T​(p.Ser773Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,612,866 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.016 (251 hom.)
• Consequence: PIK3CD NM_005026.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.369
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-9722328-C-T is Benign according to our data. Variant chr1-9722328-C-T is described in ClinVar as Benign. ClinVar VariationId is 474026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.369 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1783/152066) while in subpopulation NFE AF = 0.019 (1293/67948). AF 95% confidence interval is 0.0182. There are 12 homozygotes in GnomAd4. There are 830 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	NM_005026.5	MANE Select	c.2319C>T	p.Ser773Ser	synonymous	Exon 18 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.2319C>T	p.Ser773Ser	synonymous	Exon 17 of 23	NP_001424475.1	A0A2K8FKV1
	PIK3CD	NM_001350234.2		c.2316C>T	p.Ser772Ser	synonymous	Exon 18 of 24	NP_001337163.1	B7ZM44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.2319C>T	p.Ser773Ser	synonymous	Exon 18 of 24	ENSP00000366563.4	O00329-1
	PIK3CD	ENST00000361110.6	TSL:1	c.2391C>T	p.Ser797Ser	synonymous	Exon 17 of 23	ENSP00000354410.2	F8W9P4
	PIK3CD	ENST00000892288.1		c.2496C>T	p.Ser832Ser	synonymous	Exon 18 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1783 AN: 151950 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00377

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.00959

GnomAD2 exomes AF: 0.0105 AC: 2583 AN: 247022 AF XY: 0.0105

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00757

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00328

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0163 AC: 23838 AN: 1460800 Hom.: 251 Cov.: 35 AF XY: 0.0161 AC XY: 11666 AN XY: 726690

African (AFR) AF: 0.00284 AC: 95 AN: 33472

American (AMR) AF: 0.00768 AC: 343 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 438 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00349 AC: 301 AN: 86176

European-Finnish (FIN) AF: 0.00411 AC: 218 AN: 52984

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0195 AC: 21634 AN: 1111646

Other (OTH) AF: 0.0132 AC: 799 AN: 60324

GnomAD4 genome AF: 0.0117 AC: 1783 AN: 152066 Hom.: 12 Cov.: 32 AF XY: 0.0112 AC XY: 830 AN XY: 74338

African (AFR) AF: 0.00376 AC: 156 AN: 41520

American (AMR) AF: 0.0131 AC: 200 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5122

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10592

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0190 AC: 1293 AN: 67948

Other (OTH) AF: 0.00949 AC: 20 AN: 2108

Alfa AF: 0.0153 Hom.: 6

Bravo AF: 0.0117

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0168

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Immunodeficiency 14 (1)
-	-	1	PIK3CD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs139848768; hg19: chr1-9782386;