1-9710496-A-C

Position:

• chr1-9710496-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005026.5(PIK3CD):​c.41A>C​(p.Lys14Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.20

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 Uncertain_significance. Variant got 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1758889).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CD	NM_005026.5	c.41A>C	p.Lys14Thr	missense_variant	3/24	ENST00000377346.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CD	ENST00000377346.9	c.41A>C	p.Lys14Thr	missense_variant	3/24	1	NM_005026.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2019

This sequence change replaces lysine with threonine at codon 14 of the PIK3CD protein (p.Lys14Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PIK3CD-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	.;T;T;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.088
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	.;D;D;D;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	.;.;L;.;.
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N;.;N;.;N
REVEL	Benign	0.061
Sift	Benign	0.34	T;.;T;.;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.23	B;.;B;B;.
Vest4		0.38
MutPred		0.35		Loss of ubiquitination at K14 (P = 0.0092);Loss of ubiquitination at K14 (P = 0.0092);Loss of ubiquitination at K14 (P = 0.0092);Loss of ubiquitination at K14 (P = 0.0092);Loss of ubiquitination at K14 (P = 0.0092);
MVP		0.54
MPC		1.2
ClinPred		0.49	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.79

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: rs1647002482; hg19: chr1-9770554;