rs28390202

Positions:

chr20-8881748-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_015192.4(PLCB1):c.3550C>T(p.Leu1184Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00411 in 1,614,034 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 16 hom. )

Consequence

PLCB1
NM_015192.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 0.170

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 links:

PLCB1 (HGNC:):

PLCB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLCB1. . Gene score misZ 3.8345 (greater than the threshold 3.09). Trascript score misZ 3.6982 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 12, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, West syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044052005).

BP6

Variant 20-8881748-C-T is Benign according to our data. Variant chr20-8881748-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95688.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2, Benign=2}. Variant chr20-8881748-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (394/152262) while in subpopulation NFE AF= 0.00462 (314/68022). AF 95% confidence interval is 0.0042. There are 2 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB1	NM_015192.4 linkuse as main transcript	c.3550C>T	p.Leu1184Phe	missense_variant	32/32	ENST00000338037.11	NP_056007.1	Q9NQ66-1
PLCB1	NM_182734.3 linkuse as main transcript	c.*146C>T		3_prime_UTR_variant	33/33		NP_877398.1	Q9NQ66-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11 linkuse as main transcript	c.3550C>T	p.Leu1184Phe	missense_variant	32/32	1	NM_015192.4	ENSP00000338185.6		Q9NQ66-1

Frequencies

GnomAD3 genomes

AF:

0.00259

AC:

394

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00259

AC:

651

AN:

251264

Hom.:

AF XY:

0.00267

AC XY:

362

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.00446

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00427

AC:

6243

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

3020

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00204

Gnomad4 NFE exome

AF:

0.00525

Gnomad4 OTH exome

AF:

0.00288

GnomAD4 genome

AF:

0.00259

AC:

394

AN:

152262

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

185

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000939

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00462

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00396

Hom.:

Bravo

AF:

0.00257

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00259

AC:

314

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00371

EpiControl

AF:

0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PLCB1: BP4, BS2 -

Developmental and epileptic encephalopathy, 12

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PLCB1 NM_015192.3 exon 32 p.Leu1184Phe (c.3550C>T): This variant has not been reported in the literature but is present in 0.4% (297/64568) of European alleles in the Genome Aggregation Database, including 2 homozygotes (https://gnomad.broadinstitute.org/variant/20-8881748-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:95688). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 13, 2015

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2018

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. -

PLCB1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2022

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

0.066

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.47

N;.

REVEL

Benign

0.092

Sift

Benign

0.035

D;.

Sift4G

Benign

0.072

T;T

Polyphen

0.0060

B;.

Vest4

0.010

MVP

0.11

MPC

0.34

ClinPred

0.0017

GERP RS

-0.69

Varity_R

0.066

gMVP

0.035

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over