rs28730674

Variant names:

• chr1-9720138-A-G
• rs28730674
• NM_005026.5:c.1366A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 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:4
• Conservation: PhyloP100: 1.02
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• immunodeficiency 14b, autosomal recessive

  Inheritance: AR, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005026.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	NM_005026.5	MANE Select	c.1366A>G	p.Thr456Ala	missense	Exon 11 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.1366A>G	p.Thr456Ala	missense	Exon 10 of 23	NP_001424475.1
	PIK3CD	NM_001350234.2		c.1366A>G	p.Thr456Ala	missense	Exon 11 of 24	NP_001337163.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.1366A>G	p.Thr456Ala	missense	Exon 11 of 24	ENSP00000366563.4
	PIK3CD	ENST00000361110.6	TSL:1	c.1261A>G	p.Thr421Ala	missense	Exon 10 of 23	ENSP00000354410.2
	PIK3CD	ENST00000892288.1		c.1366A>G	p.Thr456Ala	missense	Exon 11 of 24	ENSP00000562347.1

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

GnomAD2 exomes AF: 0.00762 AC: 1912 AN: 250772 AF XY: 0.00699

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 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

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0118 AC: 529 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26136

East Asian (EAS) AF: 0.0477 AC: 1894 AN: 39700

South Asian (SAS) AF: 0.00385 AC: 332 AN: 86258

European-Finnish (FIN) AF: 0.0210 AC: 1101 AN: 52462

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000430 AC: 478 AN: 1112000

Other (OTH) AF: 0.00369 AC: 223 AN: 60386

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

African (AFR) AF: 0.0000481 AC: 2 AN: 41552

American (AMR) AF: 0.00385 AC: 59 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.0424 AC: 219 AN: 5164

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4822

European-Finnish (FIN) AF: 0.0222 AC: 236 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 67992

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00263 Hom.: 9

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 14 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	PIK3CD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		1.0
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.13
Sift	Benign	0.26	T
Sift4G	Benign	0.080	T
Polyphen		0.0	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
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

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