chr20-8132713-G-A

Position:

• chr20-8132713-G-A

Variant summary

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

The NM_015192.4(PLCB1):​c.62G>A​(p.Ser21Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S21S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCB1 NM_015192.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

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=0.10953304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCB1	NM_015192.4	c.62G>A	p.Ser21Asn	missense_variant	1/32	ENST00000338037.11
PLCB1	NM_182734.3	c.62G>A	p.Ser21Asn	missense_variant	1/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB1	ENST00000338037.11	c.62G>A	p.Ser21Asn	missense_variant	1/32	1	NM_015192.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2021

This sequence change replaces serine with asparagine at codon 21 of the PLCB1 protein (p.Ser21Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.078
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.0079
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.76	.;T;T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L;.;.;L
MutationTaster	Benign	0.69	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.61	N;N;.;.;N
REVEL	Benign	0.027
Sift	Benign	0.38	T;T;.;.;T
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.063	B;B;.;.;B
Vest4		0.11
MutPred		0.35		Loss of disorder (P = 0.0916);Loss of disorder (P = 0.0916);Loss of disorder (P = 0.0916);Loss of disorder (P = 0.0916);Loss of disorder (P = 0.0916);
MVP		0.46
MPC		0.094
ClinPred		0.28	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-8113360;