rs61755436

chr20-8788457-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015192.4(PLCB1):c.3120A>G(p.Gln1040=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,110 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (64 hom.)
• Consequence: PLCB1 NM_015192.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.958

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=-0.56).
• BP6: Variant 20-8788457-A-G is Benign according to our data. Variant chr20-8788457-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.958 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00223 (340/152344) while in subpopulation AMR AF= 0.0197 (301/15302). AF 95% confidence interval is 0.0178. There are 2 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCB1	NM_015192.4	c.3120A>G	p.Gln1040=	synonymous_variant	28/32	ENST00000338037.11
PLCB1	NM_182734.3	c.3120A>G	p.Gln1040=	synonymous_variant	28/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB1	ENST00000338037.11	c.3120A>G	p.Gln1040=	synonymous_variant	28/32	1	NM_015192.4	P1

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152226 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00764 AC: 1907 AN: 249662 Hom.: 60 AF XY: 0.00573 AC XY: 773 AN XY: 134828

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0529

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00333

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00161 AC: 2349 AN: 1460766 Hom.: 64 Cov.: 31 AF XY: 0.00132 AC XY: 959 AN XY: 726548

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0489

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.0000699

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152344 Hom.: 2 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74500

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000850 Hom.: 1

Bravo AF: 0.00496

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 03, 2017	- -

Developmental and epileptic encephalopathy, 12 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 28, 2022	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	8.4
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61755436; hg19: chr20-8769104;