rs2076689

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015192.4(PLCB1):c.1251-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,611,148 control chromosomes in the GnomAD database, including 13,162 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.098 ( 1075 hom., cov: 33)

Exomes 𝑓: 0.12 ( 12087 hom. )

Consequence

PLCB1
NM_015192.4 splice_region, intron

Scores

Splicing: ADA: 0.00002938

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.875

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 20-8716260-T-G is Benign according to our data. Variant chr20-8716260-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB1	NM_015192.4 link	c.1251-4T>G		splice_region_variant, intron_variant	Intron 12 of 31	ENST00000338037.11	NP_056007.1	Q9NQ66-1
PLCB1	NM_182734.3 link	c.1251-4T>G		splice_region_variant, intron_variant	Intron 12 of 32		NP_877398.1	Q9NQ66-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11 link	c.1251-4T>G		splice_region_variant, intron_variant	Intron 12 of 31	1	NM_015192.4	ENSP00000338185.6		Q9NQ66-1

Frequencies

GnomAD3 genomes

AF:

0.0982

AC:

14937

AN:

152138

Hom.:

1072

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0240

Gnomad AMI

AF:

0.0757

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.0845

Gnomad EAS

AF:

0.334

Gnomad SAS

AF:

0.0605

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.0803

GnomAD2 exomes

AF:

0.130

AC:

32735

AN:

251032

AF XY:

0.123

show subpopulations

Gnomad AFR exome

AF:

0.0196

Gnomad AMR exome

AF:

0.242

Gnomad ASJ exome

AF:

0.0758

Gnomad EAS exome

AF:

0.333

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.116

GnomAD4 exome

AF:

0.117

AC:

170162

AN:

1458892

Hom.:

12087

Cov.:

AF XY:

0.114

AC XY:

82876

AN XY:

725888

show subpopulations

African (AFR)

AF:

0.0170

AC:

569

AN:

33450

American (AMR)

AF:

0.235

AC:

10506

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0782

AC:

2042

AN:

26122

East Asian (EAS)

AF:

0.347

AC:

13756

AN:

39664

South Asian (SAS)

AF:

0.0507

AC:

4368

AN:

86216

European-Finnish (FIN)

AF:

0.126

AC:

6733

AN:

53402

Middle Eastern (MID)

AF:

0.0339

AC:

195

AN:

5760

European-Non Finnish (NFE)

AF:

0.113

AC:

125152

AN:

1109272

Other (OTH)

AF:

0.113

AC:

6841

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

6488

12975

19463

25950

32438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4706

9412

14118

18824

23530

<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:

0.0982

AC:

14950

AN:

152256

Hom.:

1075

Cov.:

AF XY:

0.101

AC XY:

7496

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0239

AC:

993

AN:

41568

American (AMR)

AF:

0.179

AC:

2740

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0845

AC:

293

AN:

3468

East Asian (EAS)

AF:

0.334

AC:

1730

AN:

5174

South Asian (SAS)

AF:

0.0597

AC:

288

AN:

4822

European-Finnish (FIN)

AF:

0.120

AC:

1271

AN:

10610

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7382

AN:

68004

Other (OTH)

AF:

0.0809

AC:

171

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

648

1296

1944

2592

3240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<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:

0.108

Hom.:

782

Bravo

AF:

0.103

Asia WGS

AF:

0.182

AC:

631

AN:

3478

EpiCase

AF:

0.103

EpiControl

AF:

0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

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 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:3

Dec 01, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

Developmental and epileptic encephalopathy, 12

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Early Infantile Epileptic Encephalopathy, Autosomal Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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

-0.76

CADD

Benign

5.9

(source)

DANN

Benign

0.66

PhyloP100

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000029

dbscSNV1_RF

Benign

0.0

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