rs45608240

chr20-8717804-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_015192.4(PLCB1):c.1469A>G(p.Tyr490Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,613,838 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y490Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (24 hom.)
• Consequence: PLCB1 NM_015192.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.25

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PLCB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.005054921).
• BP6: Variant 20-8717804-A-G is Benign according to our data. Variant chr20-8717804-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129902.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=3, Uncertain_significance=1}. Variant chr20-8717804-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (572/152298) while in subpopulation NFE AF= 0.00644 (438/68030). AF 95% confidence interval is 0.00594. There are 1 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCB1	NM_015192.4	c.1469A>G	p.Tyr490Cys	missense_variant	14/32	ENST00000338037.11
PLCB1	NM_182734.3	c.1469A>G	p.Tyr490Cys	missense_variant	14/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB1	ENST00000338037.11	c.1469A>G	p.Tyr490Cys	missense_variant	14/32	1	NM_015192.4	P1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00644

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00354 AC: 887 AN: 250292 Hom.: 4 AF XY: 0.00351 AC XY: 475 AN XY: 135346

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00580

Gnomad OTH exome AF: 0.00476

GnomAD4 exome AF: 0.00607 AC: 8871 AN: 1461540 Hom.: 24 Cov.: 31 AF XY: 0.00588 AC XY: 4276 AN XY: 727056

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00291

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.00728

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74484

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00644

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00556 Hom.: 4

Bravo AF: 0.00401

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00353 AC: 429

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00558

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 14, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 27, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PLCB1: PP2, BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	This variant is associated with the following publications: (PMID: 32970752) -

Early Infantile Epileptic Encephalopathy, Autosomal Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2018

This alteration is classified as 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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

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	0.049
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	13
Dann	Benign	0.69
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.84	T;T;.;T;T;T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0051	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
Polyphen		0.0010, 0.0	.;.;B;B;B;.;.;.
Vest4		0.13, 0.14, 0.13
MVP		0.32
MPC		1.3
ClinPred		0.0058	T
GERP RS		-1.8
Varity_R		0.061
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45608240; hg19: chr20-8698451; COSMIC: COSV99059812;