rs28730668

Positions:

• chr1-9717064-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_005026.5(PIK3CD):​c.886G>A​(p.Val296Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,613,934 control chromosomes in the GnomAD database, including 331 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (176 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (155 hom.)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.851

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=0.0018967688).
• BP6: Variant 1-9717064-G-A is Benign according to our data. Variant chr1-9717064-G-A is described in ClinVar as [Benign]. Clinvar id is 474036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CD	NM_005026.5	c.886G>A	p.Val296Ile	missense_variant	7/24	ENST00000377346.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CD	ENST00000377346.9	c.886G>A	p.Val296Ile	missense_variant	7/24	1	NM_005026.5	P3

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4138 AN: 152176 Hom.: 175 Cov.: 33

Gnomad AFR AF: 0.0928

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00740 AC: 1859 AN: 251366 Hom.: 77 AF XY: 0.00563 AC XY: 765 AN XY: 135890

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.00584

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00310 AC: 4536 AN: 1461640 Hom.: 155 Cov.: 33 AF XY: 0.00284 AC XY: 2067 AN XY: 727120

Gnomad4 AFR exome AF: 0.0958

Gnomad4 AMR exome AF: 0.00628

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000390

Gnomad4 OTH exome AF: 0.00672

GnomAD4 genome AF: 0.0272 AC: 4143 AN: 152294 Hom.: 176 Cov.: 33 AF XY: 0.0267 AC XY: 1988 AN XY: 74464

Gnomad4 AFR AF: 0.0927

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00687 Hom.: 45

Bravo AF: 0.0311

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0881 AC: 388

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00857 AC: 1040

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 08, 2023

- -

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	0.075
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.93
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.40	N;.;N;.;N
REVEL	Benign	0.023
Sift	Benign	0.44	T;.;T;.;T
Sift4G	Benign	0.81	T;T;T;T;T
Polyphen		0.057	B;.;B;B;.
Vest4		0.092
MVP		0.40
MPC		0.76
ClinPred		0.0030	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs28730668; hg19: chr1-9777122; COSMIC: COSV63131097; COSMIC: COSV63131097;