20-8774596-T-C

Position:

• chr20-8774596-T-C

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.2988T>C​(p.Ala996=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,613,212 control chromosomes in the GnomAD database, including 322,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30290 hom., cov: 32)
  • Exomes 𝑓: 0.63 (291715 hom.)
• Consequence: PLCB1 NM_015192.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.931

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=-0.63).
• BP6: Variant 20-8774596-T-C is Benign according to our data. Variant chr20-8774596-T-C is described in ClinVar as [Benign]. Clinvar id is 129910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-8774596-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.931 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCB1	NM_015192.4	c.2988T>C	p.Ala996=	synonymous_variant	27/32	ENST00000338037.11
PLCB1	NM_182734.3	c.2988T>C	p.Ala996=	synonymous_variant	27/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB1	ENST00000338037.11	c.2988T>C	p.Ala996=	synonymous_variant	27/32	1	NM_015192.4	P1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95395 AN: 151952 Hom.: 30263 Cov.: 32

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.756

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.640

GnomAD3 exomes AF: 0.607 AC: 152629 AN: 251346 Hom.: 47662 AF XY: 0.620 AC XY: 84222 AN XY: 135848

Gnomad AFR exome AF: 0.641

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.725

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.743

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.622

GnomAD4 exome AF: 0.629 AC: 919303 AN: 1461142 Hom.: 291715 Cov.: 43 AF XY: 0.634 AC XY: 460573 AN XY: 726860

Gnomad4 AFR exome AF: 0.646

Gnomad4 AMR exome AF: 0.442

Gnomad4 ASJ exome AF: 0.724

Gnomad4 EAS exome AF: 0.515

Gnomad4 SAS exome AF: 0.738

Gnomad4 FIN exome AF: 0.561

Gnomad4 NFE exome AF: 0.632

Gnomad4 OTH exome AF: 0.644

GnomAD4 genome AF: 0.628 AC: 95469 AN: 152070 Hom.: 30290 Cov.: 32 AF XY: 0.625 AC XY: 46493 AN XY: 74336

Gnomad4 AFR AF: 0.643

Gnomad4 AMR AF: 0.555

Gnomad4 ASJ AF: 0.713

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.756

Gnomad4 FIN AF: 0.568

Gnomad4 NFE AF: 0.639

Gnomad4 OTH AF: 0.643

Alfa AF: 0.639 Hom.: 57352

Bravo AF: 0.618

Asia WGS AF: 0.632 AC: 2198 AN: 3478

EpiCase AF: 0.649

EpiControl AF: 0.658

ClinVar

Significance: Benign

Submissions summary: Benign:11

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

not specified Benign:3

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 66% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 61. Only high quality variants are reported. -
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	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2019	- -

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	-0.63
CADD	Benign	7.7
DANN	Benign	0.60

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: rs2235613; hg19: chr20-8755243; COSMIC: COSV62038851;