rs186429469

Positions:

• chr20-8881782-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.3584A>G​(p.His1195Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000392 in 1,614,140 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (7 hom.)
• Consequence: PLCB1 NM_015192.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 6.74

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 (HGNC:):

ACMG classification

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=0.0051480234).
• BP6: Variant 20-8881782-A-G is Benign according to our data. Variant chr20-8881782-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283209.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}. Variant chr20-8881782-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000269 (41/152310) while in subpopulation SAS AF= 0.0029 (14/4820). AF 95% confidence interval is 0.00176. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.3584A>G	p.His1195Arg	missense_variant	32/32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.*180A>G		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	c.3584A>G	p.His1195Arg	missense_variant	32/32	1	NM_015192.4	ENSP00000338185.6

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000987 AC: 248 AN: 251178 Hom.: 4 AF XY: 0.00106 AC XY: 144 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.000405 AC: 592 AN: 1461830 Hom.: 7 Cov.: 31 AF XY: 0.000465 AC XY: 338 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74486

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000349 Hom.: 0

Bravo AF: 0.000412

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00113 AC: 137

EpiCase AF: 0.000382

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	PLCB1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2018	- -

Developmental and epileptic encephalopathy, 12 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 11, 2015

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 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

Jul 31, 2024

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	0.072
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.14
Sift	Benign	0.060	T;.
Sift4G	Benign	0.26	T;T
Polyphen		0.93	P;.
Vest4		0.29
MVP		0.43
MPC		0.38
ClinPred		0.11	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.35

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: rs186429469; hg19: chr20-8862429;