rs45608240

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015192.4(PLCB1):c.1469A>G(p.Tyr490Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,613,838 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 24 hom. )

Consequence

PLCB1
NM_015192.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 1.25

Variant links:

Genes affected

PLCB1 (HGNC:15917): (phospholipase C beta 1) The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PLCB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005054921).

BP6

Variant 20-8717804-A-G is Benign according to our data. Variant chr20-8717804-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129902.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=3, Uncertain_significance=1}. Variant chr20-8717804-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (572/152298) while in subpopulation NFE AF= 0.00644 (438/68030). AF 95% confidence interval is 0.00594. There are 1 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB1	NM_015192.4 link	c.1469A>G	p.Tyr490Cys	missense_variant	Exon 14 of 32	ENST00000338037.11	NP_056007.1	Q9NQ66-1
PLCB1	NM_182734.3 link	c.1469A>G	p.Tyr490Cys	missense_variant	Exon 14 of 33		NP_877398.1	Q9NQ66-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11 link	c.1469A>G	p.Tyr490Cys	missense_variant	Exon 14 of 32	1	NM_015192.4	ENSP00000338185.6		Q9NQ66-1

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

573

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00644

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00354

AC:

887

AN:

250292

Hom.:

AF XY:

0.00351

AC XY:

475

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.000989

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.00319

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00144

Gnomad NFE exome

AF:

0.00580

Gnomad OTH exome

AF:

0.00476

GnomAD4 exome

AF:

0.00607

AC:

8871

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00588

AC XY:

4276

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.00291

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00163

Gnomad4 NFE exome

AF:

0.00728

Gnomad4 OTH exome

AF:

0.00573

GnomAD4 genome

AF:

0.00376

AC:

572

AN:

152298

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00644

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00556

Hom.:

Bravo

AF:

0.00401

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00353

AC:

429

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00558

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 12

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

May 27, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Dec 21, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32970752) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PLCB1: BP4, BS2 -

Early Infantile Epileptic Encephalopathy, Autosomal Recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 17, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PLCB1-related disorder

Benign:1

Nov 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

0.049

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Uncertain

0.50

.;.;.;T;.;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.84

T;T;.;T;T;T;T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.0051

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.49

.;.;N;N;N;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.5

.;.;N;N;N;.;.;.

REVEL

Benign

0.15

Sift

Benign

0.18

.;.;T;T;T;.;.;.

Sift4G

Benign

0.18

.;T;T;T;T;T;T;T

Polyphen

0.0010, 0.0

.;.;B;B;B;.;.;.

Vest4

0.13, 0.14, 0.13

MVP

0.32

MPC

1.3

ClinPred

0.0058

GERP RS

-1.8

Varity_R

0.061

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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