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:3
• 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]

PIK3CD (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CD. . Gene score misZ 4.2747 (greater than the threshold 3.09). Trascript score misZ 6.3833 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency 14b, autosomal recessive, immunodeficiency 14, activated PI3K-delta syndrome.
• 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	Protein	UniProt
PIK3CD	NM_005026.5	c.886G>A	p.Val296Ile	missense_variant	7/24	ENST00000377346.9	NP_005017.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CD	ENST00000377346.9	c.886G>A	p.Val296Ile	missense_variant	7/24	1	NM_005026.5	ENSP00000366563.4

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Immunodeficiency 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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
DEOGEN2	Benign	0.24	.;T;T;.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	.;T;T;T;.
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;.;L;.;.
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;