3-138684716-T-C

Variant names:

• chr3-138684716-T-C
• rs771885408
• NM_006219.3:c.2224A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006219.3(PIK3CB):​c.2224A>G​(p.Met742Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PIK3CB NM_006219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CB	NM_006219.3	c.2224A>G	p.Met742Val	missense_variant	Exon 17 of 24	ENST00000674063.1	NP_006210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CB	ENST00000674063.1	c.2224A>G	p.Met742Val	missense_variant	Exon 17 of 24		NM_006219.3	ENSP00000501150.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251302 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461590 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2224A>G (p.M742V) alteration is located in exon 15 (coding exon 15) of the PIK3CB gene. This alteration results from a A to G substitution at nucleotide position 2224, causing the methionine (M) at amino acid position 742 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T;T;.
Eigen	Benign	0.097
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	2.0	M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.058	T;T;T
Sift4G	Benign	0.085	T;T;T
Polyphen		0.40	B;B;B
Vest4		0.61
MutPred		0.57		Gain of ubiquitination at K739 (P = 0.1162);Gain of ubiquitination at K739 (P = 0.1162);.;
MVP		0.92
MPC		0.89
ClinPred		0.47	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.67

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: rs771885408; hg19: chr3-138403558;