rs587777389

Variant names:

• chr1-9720793-G-A
• rs587777389
• NM_005026.5:c.1573G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_005026.5(PIK3CD):​c.1573G>A​(p.Glu525Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003522793: Experimental studies have shown that this missense change affects PIK3CD function (PMID:24165795, 28167755, 29330011).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E525G) has been classified as Likely pathogenic. The gene PIK3CD is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.01
• Publications: 49 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• immunodeficiency 14b, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for PIK3CD are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003522793: Experimental studies have shown that this missense change affects PIK3CD function (PMID: 24165795, 28167755, 29330011).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_005026.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-9720794-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 582515.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant 1-9720793-G-A is Pathogenic according to our data. Variant chr1-9720793-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 132807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1573G>A	p.Glu525Lys	missense	Exon 13 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.1573G>A	p.Glu525Lys	missense	Exon 12 of 23	NP_001424475.1	A0A2K8FKV1
	PIK3CD	NM_001350234.2		c.1570G>A	p.Glu524Lys	missense	Exon 13 of 24	NP_001337163.1	B7ZM44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.1573G>A	p.Glu525Lys	missense	Exon 13 of 24	ENSP00000366563.4	O00329-1
	PIK3CD	ENST00000361110.6	TSL:1	c.1645G>A	p.Glu549Lys	missense	Exon 12 of 23	ENSP00000354410.2	F8W9P4
	PIK3CD	ENST00000892288.1		c.1750G>A	p.Glu584Lys	missense	Exon 13 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Immunodeficiency 14 (5)
1	-	-	PIK3CD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.9	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.69	P
Vest4		0.76
MutPred		0.52		Gain of MoRF binding (P = 0.0106)
MVP		0.68
MPC		1.8
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.89
gMVP		0.65
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs587777389; hg19: chr1-9780851;