1-204424895-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001377334.1(PIK3C2B):c.4862C>G(p.Thr1621Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000318 in 1,614,208 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1621T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: PIK3C2B NM_001377334.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.72

Genes affected

PIK3C2B (HGNC:8972): (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta) The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. The PI3-kinase activity of this protein is sensitive to low nanomolar levels of the inhibitor wortmanin. The C2 domain of this protein was shown to bind phospholipids but not Ca2+, which suggests that this enzyme may function in a calcium-independent manner. [provided by RefSeq, Jul 2008]

PPP1R15B-AS1 (HGNC:55838): (PPP1R15B and PIK3C2B antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059078336).
• BP6: Variant 1-204424895-G-C is Benign according to our data. Variant chr1-204424895-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 783961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 241 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3C2B	NM_001377334.1	c.4862C>G	p.Thr1621Ser	missense_variant	33/33	ENST00000684373.1
PIK3C2B	NM_002646.4	c.4862C>G	p.Thr1621Ser	missense_variant	35/35
PIK3C2B	NM_001377335.1	c.4778C>G	p.Thr1593Ser	missense_variant	36/36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3C2B	ENST00000684373.1	c.4862C>G	p.Thr1621Ser	missense_variant	33/33		NM_001377334.1	P1
PPP1R15B-AS1	ENST00000443515.1	n.147-10442G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 241 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.00143

GnomAD3 exomes AF: 0.000402 AC: 101 AN: 251226 Hom.: 1 AF XY: 0.000228 AC XY: 31 AN XY: 135812

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 270 AN: 1461882 Hom.: 2 Cov.: 31 AF XY: 0.000151 AC XY: 110 AN XY: 727240

Gnomad4 AFR exome AF: 0.00681

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74478

Gnomad4 AFR AF: 0.00558

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000999 Hom.: 0

Bravo AF: 0.00210

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2018

- -

PIK3C2B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.099	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.21
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.014	D;D
Polyphen		0.016	B;B
Vest4		0.11
MutPred		0.32		Gain of glycosylation at T1621 (P = 0.0255);.;
MVP		0.40
MPC		0.29
ClinPred		0.028	T
GERP RS		3.3
Varity_R		0.058
gMVP		0.17

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: rs61758020; hg19: chr1-204394023;