rs61755420

Positions:

• chr1-9717541-C-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.935C>G​(p.Ser312Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,613,884 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S312S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (45 hom., cov: 32)
  • Exomes 𝑓: 0.027 (615 hom.)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.09

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 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=0.0024999976).
• BP6: Variant 1-9717541-C-G is Benign according to our data. Variant chr1-9717541-C-G is described in ClinVar as [Benign]. Clinvar id is 440066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0187 (2851/152378) while in subpopulation NFE AF= 0.027 (1834/68042). AF 95% confidence interval is 0.0259. There are 45 homozygotes in gnomad4. There are 1338 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CD	NM_005026.5	c.935C>G	p.Ser312Cys	missense_variant	8/24	ENST00000377346.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CD	ENST00000377346.9	c.935C>G	p.Ser312Cys	missense_variant	8/24	1	NM_005026.5	P3

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2853 AN: 152260 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0202 AC: 5055 AN: 250332 Hom.: 73 AF XY: 0.0203 AC XY: 2748 AN XY: 135592

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0476

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.0263

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0270 AC: 39495 AN: 1461506 Hom.: 615 Cov.: 32 AF XY: 0.0262 AC XY: 19068 AN XY: 727078

Gnomad4 AFR exome AF: 0.00391

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0467

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00270

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0271

GnomAD4 genome AF: 0.0187 AC: 2851 AN: 152378 Hom.: 45 Cov.: 32 AF XY: 0.0180 AC XY: 1338 AN XY: 74508

Gnomad4 AFR AF: 0.00507

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0496

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0238

Gnomad4 NFE AF: 0.0270

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0281 Hom.: 21

Bravo AF: 0.0196

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0299 AC: 257

ExAC AF: 0.0207 AC: 2509

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0295

EpiControl AF: 0.0313

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	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PIK3CD: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 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	0.063
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.055	.;T;D;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.33
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.054	.;T;T;T;.
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;L;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D;.;N;.;D
REVEL	Benign	0.12
Sift	Benign	0.042	D;.;D;.;D
Sift4G	Uncertain	0.029	D;D;D;D;D
Polyphen		0.0	B;.;P;B;.
Vest4		0.12
MPC		1.6
ClinPred		0.023	T
GERP RS		3.6
Varity_R		0.21
gMVP		0.55

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: rs61755420; hg19: chr1-9777599;