rs4888183

Positions:

• chr16-81859103-T-A
• chr16-81859103-T-C

Variant summary

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

The NM_002661.5(PLCG2):​c.432-13T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,517,952 control chromosomes in the GnomAD database, including 228,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23448 hom., cov: 33)
  • Exomes 𝑓: 0.55 (205146 hom.)
• Consequence: PLCG2 NM_002661.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0710

Genes affected

PLCG2 (HGNC:9066): (phospholipase C gamma 2) The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-81859103-T-A is Benign according to our data. Variant chr16-81859103-T-A is described in ClinVar as [Benign]. Clinvar id is 403318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81859103-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.432-13T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.432-13T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.553 AC: 84062 AN: 152026 Hom.: 23445 Cov.: 33

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.569

GnomAD3 exomes AF: 0.554 AC: 137831 AN: 248668 Hom.: 38483 AF XY: 0.549 AC XY: 74075 AN XY: 134924

Gnomad AFR exome AF: 0.526

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.604

Gnomad EAS exome AF: 0.635

Gnomad SAS exome AF: 0.448

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.546 AC: 745245 AN: 1365808 Hom.: 205146 Cov.: 22 AF XY: 0.544 AC XY: 372498 AN XY: 685244

Gnomad4 AFR exome AF: 0.519

Gnomad4 AMR exome AF: 0.557

Gnomad4 ASJ exome AF: 0.604

Gnomad4 EAS exome AF: 0.577

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.547

Gnomad4 OTH exome AF: 0.559

GnomAD4 genome AF: 0.553 AC: 84106 AN: 152144 Hom.: 23448 Cov.: 33 AF XY: 0.554 AC XY: 41185 AN XY: 74366

Gnomad4 AFR AF: 0.521

Gnomad4 AMR AF: 0.583

Gnomad4 ASJ AF: 0.586

Gnomad4 EAS AF: 0.610

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.609

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.567

Alfa AF: 0.559 Hom.: 4316

Bravo AF: 0.552

Asia WGS AF: 0.512 AC: 1779 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied by a panel of primary immunodeficiencies. Number of patients: 75. Only high quality variants are reported. -

Familial cold autoinflammatory syndrome 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.1
DANN	Benign	0.73

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: rs4888183; hg19: chr16-81892708; COSMIC: COSV63878556;