NM_006219.3:c.2995C>G

Variant names:

• chr3-138656222-G-C
• rs1308863979
• NM_006219.3:c.2995C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006219.3(PIK3CB):​c.2995C>G​(p.Leu999Val) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CB NM_006219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80
• Publications: 0 publications found

Genes affected

PIK3CB (HGNC:8976): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) This gene encodes an isoform of the catalytic subunit of phosphoinositide 3-kinase (PI3K). These kinases are important in signaling pathways involving receptors on the outer membrane of eukaryotic cells and are named for their catalytic subunit. The encoded protein is the catalytic subunit for PI3Kbeta (PI3KB). PI3KB has been shown to be part of the activation pathway in neutrophils which have bound immune complexes at sites of injury or infection. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006219.3. 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
	PIK3CB	NM_006219.3	MANE Select	c.2995C>G	p.Leu999Val	missense	Exon 23 of 24	NP_006210.1	P42338
	PIK3CB	NM_001437286.1		c.2995C>G	p.Leu999Val	missense	Exon 22 of 23	NP_001424215.1
	PIK3CB	NM_001437287.1		c.2995C>G	p.Leu999Val	missense	Exon 24 of 25	NP_001424216.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CB	ENST00000674063.1	MANE Select	c.2995C>G	p.Leu999Val	missense	Exon 23 of 24	ENSP00000501150.1	P42338
	PIK3CB	ENST00000477593.6	TSL:5	c.2995C>G	p.Leu999Val	missense	Exon 22 of 23	ENSP00000418143.1	P42338
	PIK3CB	ENST00000894539.1		c.2995C>G	p.Leu999Val	missense	Exon 24 of 25	ENSP00000564598.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.78		Loss of stability (P = 0.1418)
MVP		0.59
MPC		1.4
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.65
gMVP		0.77
Mutation Taster		=36/64	disease causing

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: rs1308863979; hg19: chr3-138375064;