NM_006219.3:c.2489C>T

Variant names:

• chr3-138681982-G-A
• rs750375278
• NM_006219.3:c.2489C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_006219.3(PIK3CB):​c.2489C>T​(p.Ala830Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000624 in 1,603,258 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PIK3CB NM_006219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30779415).

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.2489C>T	p.Ala830Val	missense	Exon 19 of 24	NP_006210.1	P42338
	PIK3CB	NM_001437286.1		c.2489C>T	p.Ala830Val	missense	Exon 18 of 23	NP_001424215.1
	PIK3CB	NM_001437287.1		c.2489C>T	p.Ala830Val	missense	Exon 20 of 25	NP_001424216.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CB	ENST00000674063.1	MANE Select	c.2489C>T	p.Ala830Val	missense	Exon 19 of 24	ENSP00000501150.1	P42338
	PIK3CB	ENST00000477593.6	TSL:5	c.2489C>T	p.Ala830Val	missense	Exon 18 of 23	ENSP00000418143.1	P42338
	PIK3CB	ENST00000894539.1		c.2489C>T	p.Ala830Val	missense	Exon 20 of 25	ENSP00000564598.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150856 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000286 AC: 7 AN: 244526 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000209

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: 0.00000551 AC: 8 AN: 1452402 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 722230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32910

American (AMR) AF: 0.000184 AC: 8 AN: 43554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.00 AC: 0 AN: 83904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107688

Other (OTH) AF: 0.00 AC: 0 AN: 60018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00130156), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150856 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73514

African (AFR) AF: 0.00 AC: 0 AN: 41134

American (AMR) AF: 0.000132 AC: 2 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67808

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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	Benign	0.23
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.94	P
Vest4		0.62
MutPred		0.56		Gain of ubiquitination at K828 (P = 0.1222)
MVP		0.51
MPC		0.56
ClinPred		0.25	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.78
Mutation Taster		=77/23	polymorphism

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: rs750375278; hg19: chr3-138400824;