rs28730674

chr1-9720138-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005026.5(PIK3CD):c.1366A>G(p.Thr456Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,142 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T456M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (87 hom.)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.02

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PIK3CD
• BP4: Computational evidence support a benign effect (MetaRNN=0.007569164).
• BP6: Variant 1-9720138-A-G is Benign according to our data. Variant chr1-9720138-A-G is described in ClinVar as [Benign]. Clinvar id is 474023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00392 (596/152234) while in subpopulation EAS AF= 0.0424 (219/5164). AF 95% confidence interval is 0.0378. There are 11 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CD	NM_005026.5	c.1366A>G	p.Thr456Ala	missense_variant	11/24	ENST00000377346.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CD	ENST00000377346.9	c.1366A>G	p.Thr456Ala	missense_variant	11/24	1	NM_005026.5	P3

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 596 AN: 152116 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00762 AC: 1912 AN: 250772 Hom.: 23 AF XY: 0.00699 AC XY: 949 AN XY: 135778

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0378

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00315 AC: 4601 AN: 1460908 Hom.: 87 Cov.: 33 AF XY: 0.00317 AC XY: 2302 AN XY: 726774

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0477

Gnomad4 SAS exome AF: 0.00385

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.00369

GnomAD4 genome AF: 0.00392 AC: 596 AN: 152234 Hom.: 11 Cov.: 31 AF XY: 0.00485 AC XY: 361 AN XY: 74436

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0424

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0222

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00265 Hom.: 7

Bravo AF: 0.00351

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00705 AC: 856

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

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
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	1.8
Dann	Benign	0.68
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.73	D
MetaRNN	Benign	0.0076	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.50	N;.;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.26	T;.;T;.;T
Sift4G	Benign	0.080	T;T;T;T;T
Polyphen		0.0	B;.;B;B;.
Vest4		0.26
MVP		0.67
MPC		0.92
ClinPred		0.0085	T
GERP RS		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.054
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs28730674; hg19: chr1-9780196; COSMIC: COSV63127101; COSMIC: COSV63127101;