20-8757081-T-A

Position:

• chr20-8757081-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000338037.11(PLCB1):​c.2559T>A​(p.Ser853Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PLCB1 ENST00000338037.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.48

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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=0.08548978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.2559T>A	p.Ser853Arg	missense_variant	24/32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.2559T>A	p.Ser853Arg	missense_variant	24/33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11	c.2559T>A	p.Ser853Arg	missense_variant	24/32	1	NM_015192.4	ENSP00000338185	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Developmental and epileptic encephalopathy, 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2021

This sequence change replaces serine with arginine at codon 853 of the PLCB1 protein (p.Ser853Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PLCB1-related conditions. 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	0.19
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.25	.;.;.;T;.;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T;T;.;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.085	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;.;L;L;L;.;.;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	.;.;N;N;N;.;.;.
REVEL	Benign	0.023
Sift	Benign	0.36	.;.;T;T;T;.;.;.
Sift4G	Benign	0.45	.;T;T;T;T;T;T;T
Polyphen		0.18, 0.0010	.;.;B;B;B;.;.;.
Vest4		0.23, 0.27, 0.23
MutPred		0.19		.;.;Loss of phosphorylation at S853 (P = 0.0047);Loss of phosphorylation at S853 (P = 0.0047);Loss of phosphorylation at S853 (P = 0.0047);.;.;.;
MVP		0.29
MPC		0.35
ClinPred		0.21	T
GERP RS		2.1
Varity_R		0.075
gMVP		0.16

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

Other links and lift over

dbSNP: rs753642857; hg19: chr20-8737728;