20-8737175-C-G

Position:

• chr20-8737175-C-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.2191C>G​(p.Pro731Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,564 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0092 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (14 hom.)
• Consequence: PLCB1 NM_015192.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.28

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 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=0.0059148073).
• BP6: Variant 20-8737175-C-G is Benign according to our data. Variant chr20-8737175-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129904.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00917 (1396/152206) while in subpopulation AFR AF= 0.0311 (1292/41510). AF 95% confidence interval is 0.0297. There are 23 homozygotes in gnomad4. There are 681 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.2191C>G	p.Pro731Ala	missense_variant	20/32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.2191C>G	p.Pro731Ala	missense_variant	20/33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11	c.2191C>G	p.Pro731Ala	missense_variant	20/32	1	NM_015192.4	ENSP00000338185	P1

Frequencies

GnomAD3 genomes AF: 0.00919 AC: 1398 AN: 152088 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00286 AC: 719 AN: 251204 Hom.: 13 AF XY: 0.00214 AC XY: 291 AN XY: 135752

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00884

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00107 AC: 1563 AN: 1461358 Hom.: 14 Cov.: 31 AF XY: 0.000924 AC XY: 672 AN XY: 726974

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00881

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00917 AC: 1396 AN: 152206 Hom.: 23 Cov.: 33 AF XY: 0.00915 AC XY: 681 AN XY: 74428

Gnomad4 AFR AF: 0.0311

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00176 Hom.: 2

Bravo AF: 0.0105

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00336 AC: 408

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PLCB1: PP2, BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	This variant is associated with the following publications: (PMID: 32970752) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 06, 2018	- -

Early Infantile Epileptic Encephalopathy, Autosomal Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2016

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. -

Developmental and epileptic encephalopathy, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.69	.;.;.;D;.;T;.;T;T
Eigen	Benign	-0.0061
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;D;D;D;D
MetaRNN	Benign	0.0059	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;.;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.8	.;.;D;D;D;.;.;.;D
REVEL	Benign	0.12
Sift	Benign	0.078	.;.;T;T;T;.;.;.;T
Sift4G	Benign	0.16	.;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;.;B;B;B;.;.;.;.
Vest4		0.12, 0.12, 0.13
MVP		0.51
MPC		1.1
ClinPred		0.033	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.34

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: rs61755434; hg19: chr20-8717822;