rs397518423

Variant names:

• chr1-9726972-G-A
• rs397518423
• NM_005026.5:c.3061G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM2 PP5_Very_Strong

The NM_005026.5(PIK3CD):​c.3061G>A​(p.Glu1021Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000653771: Experimental studies have shown that this missense change affects PIK3CD function (PMID:24136356, 24165795, 26732860)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:30
• Conservation: PhyloP100: 10.0
• Publications: 183 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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000653771: Experimental studies have shown that this missense change affects PIK3CD function (PMID: 24136356, 24165795, 26732860).; SCV000803590: Well-established functional studies show a deleterious effect (PMID:24136356).; SCV001468433: In vitro functional studies also predict that this variant will impact the protein affecting binding and resulting in a gain of function effect (Angulo 2013 PMID:24136356, Lucas 2014 PMID:24165795).; SCV002318629: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24136356, 24165795).; SCV000329467: Published functional studies demonstrate this variant enhances membrane association and kinase activity of the PIK3CD protein, consistent with a gain-of-function effect (Angulo et al., 2013; Avery et al., 2018).; SCV000604662: in vitro and in vivo functional assays demonstrate the variant to be a gain of function, with enhanced membrane association, PIP3 production and PI3K pathway activation (Angulo 2013, Lucas 2014). PMID: 24165795; SCV003920323: In vitro functional studies also predict that this variant will impact the protein affecting binding and resulting in a gain of function effect (Angulo 2013 PMID:24136356, Lucas 2014 PMID:24165795).; SCV005006182: Functional studies have been performed that suggest this variant alters protein function (Angulo, 2013; Lucas, 2014).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005026.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-9726972-G-A is Pathogenic according to our data. Variant chr1-9726972-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 88675.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.3061G>A	p.Glu1021Lys	missense	Exon 24 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.3061G>A	p.Glu1021Lys	missense	Exon 23 of 23	NP_001424475.1	A0A2K8FKV1
	PIK3CD	NM_001350234.2		c.3058G>A	p.Glu1020Lys	missense	Exon 24 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.3061G>A	p.Glu1021Lys	missense	Exon 24 of 24	ENSP00000366563.4	O00329-1
	PIK3CD	ENST00000361110.6	TSL:1	c.3133G>A	p.Glu1045Lys	missense	Exon 23 of 23	ENSP00000354410.2	F8W9P4
	PIK3CD	ENST00000892288.1		c.3238G>A	p.Glu1080Lys	missense	Exon 24 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251100 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111918

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
16	-	-	Immunodeficiency 14 (16)
11	-	-	not provided (11)
1	-	-	Combined immunodeficiency with faciooculoskeletal anomalies;C3714976:Immunodeficiency 14;C5543301:Immunodeficiency 14b, autosomal recessive (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Inherited Immunodeficiency Diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.9	L
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.078	T
Polyphen		1.0	D
Vest4		0.54
MutPred		0.46		Gain of MoRF binding (P = 0.013)
MVP		0.88
MPC		2.2
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.90
gMVP		0.95
Mutation Taster		=14/86	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: rs397518423; hg19: chr1-9787030; COSMIC: COSV63126880; COSMIC: COSV63126880;