rs151006778

chr20-8657216-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015192.4(PLCB1):c.627A>G(p.Pro209=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,609,810 control chromosomes in the GnomAD database, including 33 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 0.00070 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (31 hom.)
• Consequence: PLCB1 NM_015192.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0790

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 20-8657216-A-G is Benign according to our data. Variant chr20-8657216-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 339497.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.079 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000703 (107/152254) while in subpopulation EAS AF= 0.00984 (51/5184). AF 95% confidence interval is 0.00769. There are 2 homozygotes in gnomad4. There are 57 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.627A>G	p.Pro209=	synonymous_variant	8/32	ENST00000338037.11
PLCB1	NM_182734.3	c.627A>G	p.Pro209=	synonymous_variant	8/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB1	ENST00000338037.11	c.627A>G	p.Pro209=	synonymous_variant	8/32	1	NM_015192.4	P1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152136 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000442 AC: 111 AN: 251116 Hom.: 0 AF XY: 0.000479 AC XY: 65 AN XY: 135736

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00174

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000867 AC: 1264 AN: 1457556 Hom.: 31 Cov.: 28 AF XY: 0.000857 AC XY: 622 AN XY: 725388

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0249

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.000515

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152254 Hom.: 2 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74460

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00984

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000443 Hom.: 0

Bravo AF: 0.000446

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2016

This alteration is classified as likely 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	11
Dann	Benign	0.77

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: rs151006778; hg19: chr20-8637863; COSMIC: COSV100570144; COSMIC: COSV100570144;