20-8132322-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_015192.4(PLCB1):c.-330C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 207,664 control chromosomes in the GnomAD database, including 13 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 0.0065 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (1 hom.)
• Consequence: PLCB1 NM_015192.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.70

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 20-8132322-C-T is Benign according to our data. Variant chr20-8132322-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 897290.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00648 (986/152212) while in subpopulation NFE AF= 0.00984 (669/67978). AF 95% confidence interval is 0.00922. There are 12 homozygotes in gnomad4. There are 506 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCB1	NM_015192.4	c.-330C>T		5_prime_UTR_variant	1/32	ENST00000338037.11
PLCB1	NM_182734.3	c.-330C>T		5_prime_UTR_variant	1/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB1	ENST00000338037.11	c.-330C>T		5_prime_UTR_variant	1/32	1	NM_015192.4	P1

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 986 AN: 152104 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00984

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00692 AC: 384 AN: 55452 Hom.: 1 Cov.: 0 AF XY: 0.00738 AC XY: 211 AN XY: 28588

Gnomad4 AFR exome AF: 0.000578

Gnomad4 AMR exome AF: 0.000690

Gnomad4 ASJ exome AF: 0.000467

Gnomad4 EAS exome AF: 0.000248

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.00787

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.00648 AC: 986 AN: 152212 Hom.: 12 Cov.: 32 AF XY: 0.00680 AC XY: 506 AN XY: 74402

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0202

Gnomad4 NFE AF: 0.00984

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.0139 Hom.: 5

Bravo AF: 0.00442

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PLCB1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	- -

Developmental and epileptic encephalopathy, 12 Uncertain: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
Cadd	Benign	20
Dann	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs532302075; hg19: chr20-8112969;