chr20-8716260-T-G

Position:

• chr20-8716260-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015192.4(PLCB1):​c.1251-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,611,148 control chromosomes in the GnomAD database, including 13,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (1075 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12087 hom.)
• Consequence: PLCB1 NM_015192.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002938
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.875

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 20-8716260-T-G is Benign according to our data. Variant chr20-8716260-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 129901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-8716260-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.1251-4T>G		splice_region_variant, intron_variant		ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.1251-4T>G		splice_region_variant, intron_variant			NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11	c.1251-4T>G		splice_region_variant, intron_variant		1	NM_015192.4	ENSP00000338185.6

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 14937 AN: 152138 Hom.: 1072 Cov.: 33

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.0845

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.0605

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0803

GnomAD3 exomes AF: 0.130 AC: 32735 AN: 251032 Hom.: 3077 AF XY: 0.123 AC XY: 16633 AN XY: 135658

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.242

Gnomad ASJ exome AF: 0.0758

Gnomad EAS exome AF: 0.333

Gnomad SAS exome AF: 0.0494

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.117 AC: 170162 AN: 1458892 Hom.: 12087 Cov.: 30 AF XY: 0.114 AC XY: 82876 AN XY: 725888

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.0782

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.0507

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.0982 AC: 14950 AN: 152256 Hom.: 1075 Cov.: 33 AF XY: 0.101 AC XY: 7496 AN XY: 74448

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.0845

Gnomad4 EAS AF: 0.334

Gnomad4 SAS AF: 0.0597

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.0809

Alfa AF: 0.109 Hom.: 715

Bravo AF: 0.103

Asia WGS AF: 0.182 AC: 631 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	- -

Developmental and epileptic encephalopathy, 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Early Infantile Epileptic Encephalopathy, Autosomal Recessive Benign:1

Likely benign, 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 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.9
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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: rs2076689; hg19: chr20-8696907; COSMIC: COSV62043365;