rs61755420

Variant names:

• chr1-9717541-C-G
• rs61755420
• NM_005026.5:c.935C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. 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:4
• 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 -20 ACMG points.

• 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 rank	MANE	Protein	UniProt
PIK3CD	NM_005026.5	c.935C>G	p.Ser312Cys	missense_variant	Exon 8 of 24	ENST00000377346.9	NP_005017.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CD	ENST00000377346.9	c.935C>G	p.Ser312Cys	missense_variant	Exon 8 of 24	1	NM_005026.5	ENSP00000366563.4

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	PIK3CD: BP4, BS1, BS2 -

Immunodeficiency 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

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;.;.
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;