1-204424895-G-C

Position:

chr1-204424895-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.72

Variant links:

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]

PIK3C2B links:

PPP1R15B-AS1 (HGNC:):

PPP1R15B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 243 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3C2B	NM_001377334.1 linkuse as main transcript	c.4862C>G	p.Thr1621Ser	missense_variant	33/33	ENST00000684373.1	NP_001364263.1
PIK3C2B	NM_002646.4 linkuse as main transcript	c.4862C>G	p.Thr1621Ser	missense_variant	35/35		NP_002637.3	O00750A2RUF7Q4LE65
PIK3C2B	NM_001377335.1 linkuse as main transcript	c.4778C>G	p.Thr1593Ser	missense_variant	36/36		NP_001364264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3C2B	ENST00000684373.1 linkuse as main transcript	c.4862C>G	p.Thr1621Ser	missense_variant	33/33		NM_001377334.1	ENSP00000507222.1		O00750

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

241

AN:

152208

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000228

AC XY:

AN XY:

135812

show subpopulations

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.:

Cov.:

AF XY:

0.000151

AC XY:

110

AN XY:

727240

show subpopulations

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.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74478

show subpopulations

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.:

Bravo

AF:

0.00210

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 10, 2018

- -

PIK3C2B-related disorder

Benign:1

Likely benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.099

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.020

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

N;.

PrimateAI

Benign

0.47

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over