NM_015192.4:c.28G>T

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.28G>T(p.Ala10Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,612,474 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A10V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 4 hom. )

Consequence

PLCB1
NM_015192.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 8.49

Publications

10 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=0.041476816).

BP6

Variant 20-8132679-G-T is Benign according to our data. Variant chr20-8132679-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410075.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000131 (20/152168) while in subpopulation SAS AF = 0.00062 (3/4836). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015192.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB1	NM_015192.4	MANE Select	c.28G>T	p.Ala10Ser	missense	Exon 1 of 32	NP_056007.1
	PLCB1	NM_182734.3		c.28G>T	p.Ala10Ser	missense	Exon 1 of 33	NP_877398.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCB1	ENST00000338037.11	TSL:1 MANE Select	c.28G>T	p.Ala10Ser	missense	Exon 1 of 32	ENSP00000338185.6
PLCB1	ENST00000378637.6	TSL:1	c.28G>T	p.Ala10Ser	missense	Exon 1 of 32	ENSP00000367904.2
PLCB1	ENST00000378641.7	TSL:1	c.28G>T	p.Ala10Ser	missense	Exon 1 of 33	ENSP00000367908.3

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000319

AC:

AN:

247682

AF XY:

0.000461

show subpopulations

Gnomad AFR exome

AF:

0.0000629

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000162

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000307

AC:

449

AN:

1460306

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

274

AN XY:

726536

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33396

American (AMR)

AF:

0.0000672

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00202

AC:

174

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000231

AC:

257

AN:

1111218

Other (OTH)

AF:

0.000199

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000620

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

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:

0.000258

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 12 (2)

Inborn genetic diseases (1)

not provided (1)

PLCB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.7

PhyloP100

8.5

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.75

REVEL

Benign

0.14

Sift

Benign

0.11

Sift4G

Benign

0.32

Polyphen

1.0

Vest4

0.43

MVP

0.37

MPC

0.095

ClinPred

0.093

GERP RS

4.8

PromoterAI

0.0096

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.30

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over