rs2294597

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015192.4(PLCB1):c.3337C>T(p.Leu1113Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,600,448 control chromosomes in the GnomAD database, including 72,118 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1113L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.25 ( 5335 hom., cov: 33)

Exomes 𝑓: 0.30 ( 66783 hom. )

Consequence

PLCB1
NM_015192.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0007654

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.43

Publications

18 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 20-8790175-C-T is Benign according to our data. Variant chr20-8790175-C-T is described in ClinVar as Benign. ClinVar VariationId is 129914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB1	NM_015192.4 link	c.3337C>T	p.Leu1113Leu	splice_region_variant, synonymous_variant	Exon 31 of 32	ENST00000338037.11	NP_056007.1	Q9NQ66-1
PLCB1	NM_182734.3 link	c.3337C>T	p.Leu1113Leu	splice_region_variant, synonymous_variant	Exon 31 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.3337C>T	p.Leu1113Leu	splice_region_variant, synonymous_variant	Exon 31 of 32	1	NM_015192.4	ENSP00000338185.6		Q9NQ66-1

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38220

AN:

151918

Hom.:

5336

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.218

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.300

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.233

GnomAD2 exomes

AF:

0.274

AC:

67376

AN:

245544

AF XY:

0.283

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.196

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.158

Gnomad FIN exome

AF:

0.287

Gnomad NFE exome

AF:

0.312

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.299

AC:

433600

AN:

1448412

Hom.:

66783

Cov.:

AF XY:

0.302

AC XY:

217815

AN XY:

720770

show subpopulations

African (AFR)

AF:

0.138

AC:

4579

AN:

33098

American (AMR)

AF:

0.198

AC:

8800

AN:

44476

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

7895

AN:

26002

East Asian (EAS)

AF:

0.157

AC:

6183

AN:

39378

South Asian (SAS)

AF:

0.341

AC:

29139

AN:

85398

European-Finnish (FIN)

AF:

0.288

AC:

15337

AN:

53164

Middle Eastern (MID)

AF:

0.224

AC:

1290

AN:

5754

European-Non Finnish (NFE)

AF:

0.312

AC:

343238

AN:

1101310

Other (OTH)

AF:

0.286

AC:

17139

AN:

59832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

12695

25390

38085

50780

63475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10978

21956

32934

43912

54890

<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:

0.251

AC:

38228

AN:

152036

Hom.:

5335

Cov.:

AF XY:

0.251

AC XY:

18642

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.142

AC:

5902

AN:

41486

American (AMR)

AF:

0.217

AC:

3324

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

968

AN:

3468

East Asian (EAS)

AF:

0.156

AC:

805

AN:

5170

South Asian (SAS)

AF:

0.352

AC:

1696

AN:

4818

European-Finnish (FIN)

AF:

0.300

AC:

3164

AN:

10546

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.318

AC:

21612

AN:

67954

Other (OTH)

AF:

0.234

AC:

493

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1457

2913

4370

5826

7283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<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:

0.293

Hom.:

17581

Bravo

AF:

0.238

Asia WGS

AF:

0.259

AC:

903

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 12

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 24, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Early Infantile Epileptic Encephalopathy, Autosomal Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

1.4

PromoterAI

-0.022

Neutral

(source)

Mutation Taster

=71/29

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00077

dbscSNV1_RF

Benign

0.19

Splicevardb

2.0

SpliceAI score (max)

0.040

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