rs28730671

chr1-9717611-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005026.5(PIK3CD):c.1005C>T(p.Ala335=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,052 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (108 hom.)
• Consequence: PIK3CD NM_005026.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.34

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-9717611-C-T is Benign according to our data. Variant chr1-9717611-C-T is described in ClinVar as [Benign]. Clinvar id is 474022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00528 (805/152320) while in subpopulation EAS AF= 0.0423 (219/5176). AF 95% confidence interval is 0.0377. There are 18 homozygotes in gnomad4. There are 530 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CD	NM_005026.5	c.1005C>T	p.Ala335=	synonymous_variant	8/24	ENST00000377346.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CD	ENST00000377346.9	c.1005C>T	p.Ala335=	synonymous_variant	8/24	1	NM_005026.5	P3

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 805 AN: 152202 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0422

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00918 AC: 2302 AN: 250708 Hom.: 30 AF XY: 0.00853 AC XY: 1158 AN XY: 135750

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0373

Gnomad SAS exome AF: 0.00493

Gnomad FIN exome AF: 0.0377

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00767

GnomAD4 exome AF: 0.00383 AC: 5595 AN: 1461732 Hom.: 108 Cov.: 32 AF XY: 0.00385 AC XY: 2800 AN XY: 727174

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0474

Gnomad4 SAS exome AF: 0.00464

Gnomad4 FIN exome AF: 0.0372

Gnomad4 NFE exome AF: 0.000465

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.00528 AC: 805 AN: 152320 Hom.: 18 Cov.: 32 AF XY: 0.00712 AC XY: 530 AN XY: 74480

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0423

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0411

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00352

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 24, 2021

- -

Combined immunodeficiency with faciooculoskeletal anomalies;C3714976:Immunodeficiency 14;C5543301:Immunodeficiency 14b, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 28, 2022

- -

PIK3CD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.61
Dann	Benign	0.92

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

LitVar

Other links and lift over

dbSNP: rs28730671; hg19: chr1-9777669; COSMIC: COSV100739993; COSMIC: COSV100739993;