3-138656256-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_006219.3(PIK3CB):c.2961G>T(p.Glu987Asp) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CB NM_006219.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.353

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PIK3CB
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 3-138656256-C-A is Pathogenic according to our data. Variant chr3-138656256-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 638630.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CB	NM_006219.3	c.2961G>T	p.Glu987Asp	missense_variant	23/24	ENST00000674063.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CB	ENST00000674063.1	c.2961G>T	p.Glu987Asp	missense_variant	23/24		NM_006219.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

NK-cell enteropathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Jul 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D;D;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	N;N;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.96	D;D;P
Vest4		0.84
MutPred		0.60		Gain of MoRF binding (P = 0.2572);Gain of MoRF binding (P = 0.2572);.;
MVP		0.90
MPC		0.99
ClinPred		0.99	D
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.82

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: rs1577033077; hg19: chr3-138375098;