rs2294597

chr20-8790175-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015192.4(PLCB1):c.3337C>T(p.Leu1113=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,600,448 control chromosomes in the GnomAD database, including 72,118 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1113L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.25 (5335 hom., cov: 33)
  • Exomes 𝑓: 0.30 (66783 hom.)
• Consequence: PLCB1 NM_015192.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0007654
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.43

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 20-8790175-C-T is Benign according to our data. Variant chr20-8790175-C-T is described in ClinVar as [Benign]. Clinvar id is 129914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-8790175-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCB1	NM_015192.4	c.3337C>T	p.Leu1113=	splice_region_variant, synonymous_variant	31/32	ENST00000338037.11
PLCB1	NM_182734.3	c.3337C>T	p.Leu1113=	splice_region_variant, synonymous_variant	31/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB1	ENST00000338037.11	c.3337C>T	p.Leu1113=	splice_region_variant, synonymous_variant	31/32	1	NM_015192.4	P1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38220 AN: 151918 Hom.: 5336 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.274 AC: 67376 AN: 245544 Hom.: 9654 AF XY: 0.283 AC XY: 37557 AN XY: 132654

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.158

Gnomad SAS exome AF: 0.344

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.299 AC: 433600 AN: 1448412 Hom.: 66783 Cov.: 28 AF XY: 0.302 AC XY: 217815 AN XY: 720770

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.304

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.251 AC: 38228 AN: 152036 Hom.: 5335 Cov.: 33 AF XY: 0.251 AC XY: 18642 AN XY: 74290

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.300

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.234

Alfa AF: 0.301 Hom.: 12935

Bravo AF: 0.238

Asia WGS AF: 0.259 AC: 903 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Early Infantile Epileptic Encephalopathy, Autosomal Recessive Benign:1

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	-0.49
Cadd	Benign	12
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00077
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.040		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: rs2294597; hg19: chr20-8770822; COSMIC: COSV62057501; COSMIC: COSV62057501;