1-9717608-C-G

Position:

• chr1-9717608-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_005026.5(PIK3CD):​c.1002C>G​(p.Asn334Lys) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. N334N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.927

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 Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_005026.5 (PIK3CD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 132806
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 1-9717608-C-G is Pathogenic according to our data. Variant chr1-9717608-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 578525.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CD	NM_005026.5	c.1002C>G	p.Asn334Lys	missense_variant	8/24	ENST00000377346.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CD	ENST00000377346.9	c.1002C>G	p.Asn334Lys	missense_variant	8/24	1	NM_005026.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 334 of the PIK3CD protein (p.Asn334Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of activated PIK3 delta syndrome (PMID: 24165795, 35753512; Invitae; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 578525). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIK3CD protein function with a positive predictive value of 80%. This variant disrupts the p.Asn334 amino acid residue in PIK3CD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24165795, 28167755). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.091	.;T;D;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;D;.
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.9	.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.5	D;.;D;.;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.77
MutPred		0.40		Gain of methylation at N299 (P = 0.0143);Gain of methylation at N299 (P = 0.0143);.;Gain of methylation at N299 (P = 0.0143);Gain of methylation at N299 (P = 0.0143);
MVP		0.88
MPC		1.7
ClinPred		1.0	D
GERP RS		-7.4
Varity_R		0.93
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs28730670; hg19: chr1-9777666;