rs190019296

Positions:

chr20-8881788-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4_StrongBS1_Supporting

The ENST00000338037.11(PLCB1):c.3590C>T(p.Thr1197Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1197A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PLCB1
ENST00000338037.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.047829032).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000788 (12/152288) while in subpopulation AFR AF= 0.000241 (10/41568). AF 95% confidence interval is 0.00013. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB1	NM_015192.4 linkuse as main transcript	c.3590C>T	p.Thr1197Ile	missense_variant	32/32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3 linkuse as main transcript	c.*186C>T		3_prime_UTR_variant	33/33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11 linkuse as main transcript	c.3590C>T	p.Thr1197Ile	missense_variant	32/32	1	NM_015192.4	ENSP00000338185	P1	Q9NQ66-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251206

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2016

The p.T1197I variant (also known as c.3590C>T), located in coding exon 32 of the PLCB1 gene, results from a C to T substitution at nucleotide position 3590. The threonine at codon 1197 is replaced by isoleucine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs190019296. Based on data from the 1000 Genomes Project, the T allele has an overall frequency of approximately 0% (0/2098) total alleles studied.. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Developmental and epileptic encephalopathy, 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2022

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1197 of the PLCB1 protein (p.Thr1197Ile). This variant is present in population databases (rs190019296, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PLCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 471509). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.062

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.86

N;.

REVEL

Benign

0.053

Sift

Benign

0.068

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.010

B;.

Vest4

0.094

MVP

0.17

MPC

0.34

ClinPred

0.11

GERP RS

6.0

Varity_R

0.13

gMVP

0.093

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

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