20-8132322-C-T

Variant names:

• chr20-8132322-C-T
• rs532302075
• NM_015192.4:c.-330C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 12

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.-330C>T		5_prime_UTR_variant	Exon 1 of 32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.-330C>T		5_prime_UTR_variant	Exon 1 of 33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11	c.-330C>T		5_prime_UTR_variant	Exon 1 of 32	1	NM_015192.4	ENSP00000338185.6

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

African (AFR) AF: 0.000578 AC: 1 AN: 1730

American (AMR) AF: 0.000690 AC: 1 AN: 1450

Ashkenazi Jewish (ASJ) AF: 0.000467 AC: 1 AN: 2142

East Asian (EAS) AF: 0.000248 AC: 1 AN: 4032

South Asian (SAS) AF: 0.00 AC: 0 AN: 614

European-Finnish (FIN) AF: 0.0158 AC: 73 AN: 4630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 332

European-Non Finnish (NFE) AF: 0.00787 AC: 290 AN: 36826

Other (OTH) AF: 0.00460 AC: 17 AN: 3696

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

African (AFR) AF: 0.00128 AC: 53 AN: 41556

American (AMR) AF: 0.00222 AC: 34 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.0202 AC: 214 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00984 AC: 669 AN: 67978

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

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

Dec 07, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PLCB1: BS2 -

Developmental and epileptic encephalopathy, 12 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.7
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs532302075; hg19: chr20-8112969;