chr20-8774575-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_015192.4(PLCB1):c.2967G>A(p.Thr989Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 1,613,416 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0071 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 56 hom. )

Consequence

PLCB1
NM_015192.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -2.23

Publications

4 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 20-8774575-G-A is Benign according to our data. Variant chr20-8774575-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129909.

BP7

Synonymous conserved (PhyloP=-2.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00708 (1078/152262) while in subpopulation AFR AF = 0.00804 (334/41540). AF 95% confidence interval is 0.00733. There are 6 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB1	NM_015192.4 link	c.2967G>A	p.Thr989Thr	synonymous_variant	Exon 27 of 32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3 link	c.2967G>A	p.Thr989Thr	synonymous_variant	Exon 27 of 33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11 link	c.2967G>A	p.Thr989Thr	synonymous_variant	Exon 27 of 32	1	NM_015192.4	ENSP00000338185.6

Frequencies

GnomAD3 genomes

AF:

0.00708

AC:

1077

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00806

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.00760

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00666

AC:

1673

AN:

251280

AF XY:

0.00682

show subpopulations

Gnomad AFR exome

AF:

0.00806

Gnomad AMR exome

AF:

0.00691

Gnomad ASJ exome

AF:

0.0178

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00819

Gnomad OTH exome

AF:

0.00995

GnomAD4 exome

AF:

0.00647

AC:

9451

AN:

1461154

Hom.:

Cov.:

AF XY:

0.00660

AC XY:

4795

AN XY:

726890

show subpopulations

African (AFR)

AF:

0.0102

AC:

340

AN:

33474

American (AMR)

AF:

0.00756

AC:

338

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

420

AN:

26118

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.00353

AC:

304

AN:

86124

European-Finnish (FIN)

AF:

0.000993

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.0265

AC:

153

AN:

5766

European-Non Finnish (NFE)

AF:

0.00661

AC:

7342

AN:

1111500

Other (OTH)

AF:

0.00825

AC:

498

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

495

990

1484

1979

2474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.00708

AC:

1078

AN:

152262

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

486

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00804

AC:

334

AN:

41540

American (AMR)

AF:

0.00765

AC:

117

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00186

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00760

AC:

517

AN:

68018

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00834

Hom.:

Bravo

AF:

0.00816

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00986

EpiControl

AF:

0.0111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 21, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Sep 08, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLCB1: BP4, BP7, 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

Apr 15, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Developmental and epileptic encephalopathy, 12

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.1

(source)

DANN

Benign

0.84

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism

(source)

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

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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