chr20-8717804-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y490Y) has been classified as Likely benign.

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

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 12
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PLCB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129902.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 24 AD,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

GnomAD2 exomes

AF:

0.00354

AC:

887

AN:

250292

AF XY:

0.00351

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 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

African (AFR)

AF:

0.000598

AC:

AN:

33456

American (AMR)

AF:

0.00282

AC:

126

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39686

South Asian (SAS)

AF:

0.00126

AC:

109

AN:

86222

European-Finnish (FIN)

AF:

0.00163

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00728

AC:

8099

AN:

1111864

Other (OTH)

AF:

0.00573

AC:

346

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

424

849

1273

1698

2122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

316

632

948

1264

1580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00376

AC:

572

AN:

152298

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41566

American (AMR)

AF:

0.00196

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00644

AC:

438

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00500

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

- -

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

- -

May 12, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

(source)

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;.;.;.

PhyloP100

1.2

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

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over