rs13333716

Positions:

• chr16-81895922-C-G

Variant summary

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

The NM_002661.5(PLCG2):​c.1188C>G​(p.Thr396Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0696 in 1,613,924 control chromosomes in the GnomAD database, including 4,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (375 hom., cov: 31)
  • Exomes 𝑓: 0.070 (4020 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.194

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]

PLCG2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 16-81895922-C-G is Benign according to our data. Variant chr16-81895922-C-G is described in ClinVar as [Benign]. Clinvar id is 403321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81895922-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.194 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.1188C>G	p.Thr396Thr	synonymous_variant	13/33	ENST00000564138.6	NP_002652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.1188C>G	p.Thr396Thr	synonymous_variant	13/33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.0651 AC: 9901 AN: 152010 Hom.: 372 Cov.: 31

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0479

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0724

Gnomad OTH AF: 0.0484

GnomAD3 exomes AF: 0.0525 AC: 13089 AN: 249510 Hom.: 405 AF XY: 0.0518 AC XY: 7016 AN XY: 135374

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0394

Gnomad EAS exome AF: 0.000222

Gnomad SAS exome AF: 0.0278

Gnomad FIN exome AF: 0.0517

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0540

GnomAD4 exome AF: 0.0700 AC: 102330 AN: 1461796 Hom.: 4020 Cov.: 33 AF XY: 0.0684 AC XY: 49743 AN XY: 727202

Gnomad4 AFR exome AF: 0.0824

Gnomad4 AMR exome AF: 0.0364

Gnomad4 ASJ exome AF: 0.0389

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0274

Gnomad4 FIN exome AF: 0.0514

Gnomad4 NFE exome AF: 0.0788

Gnomad4 OTH exome AF: 0.0661

GnomAD4 genome AF: 0.0652 AC: 9920 AN: 152128 Hom.: 375 Cov.: 31 AF XY: 0.0629 AC XY: 4674 AN XY: 74364

Gnomad4 AFR AF: 0.0812

Gnomad4 AMR AF: 0.0442

Gnomad4 ASJ AF: 0.0392

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0256

Gnomad4 FIN AF: 0.0479

Gnomad4 NFE AF: 0.0724

Gnomad4 OTH AF: 0.0479

Alfa AF: 0.0673 Hom.: 134

Bravo AF: 0.0661

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.0715

EpiControl AF: 0.0722

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Familial cold autoinflammatory syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.5
DANN	Benign	0.54

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: rs13333716; hg19: chr16-81929527;