16-81921184-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002661.5(PLCG2):c.2236-14C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 1,490,582 control chromosomes in the GnomAD database, including 242,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 20797 hom., cov: 31)

Exomes 𝑓: 0.57 ( 221362 hom. )

Consequence

PLCG2
NM_002661.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.948

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-81921184-C-G is Benign according to our data. Variant chr16-81921184-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 403323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81921184-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.2236-14C>G	intron_variant	Intron 20 of 32	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.2236-14C>G	intron_variant	Intron 21 of 33		NP_001412678.1
PLCG2	NM_001425750.1 link	c.2236-14C>G	intron_variant	Intron 20 of 32		NP_001412679.1
PLCG2	NM_001425751.1 link	c.2236-14C>G	intron_variant	Intron 21 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.2236-14C>G		intron_variant	Intron 20 of 32	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.496

AC:

75191

AN:

151620

Hom.:

20800

Cov.:

show subpopulations

Gnomad AFR

AF:

0.225

Gnomad AMI

AF:

0.488

Gnomad AMR

AF:

0.655

Gnomad ASJ

AF:

0.599

Gnomad EAS

AF:

0.778

Gnomad SAS

AF:

0.564

Gnomad FIN

AF:

0.561

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.580

Gnomad OTH

AF:

0.557

GnomAD3 exomes

AF:

0.595

AC:

141304

AN:

237632

Hom.:

42541

AF XY:

0.594

AC XY:

76689

AN XY:

129028

show subpopulations

Gnomad AFR exome

AF:

0.234

Gnomad AMR exome

AF:

0.725

Gnomad ASJ exome

AF:

0.606

Gnomad EAS exome

AF:

0.780

Gnomad SAS exome

AF:

0.557

Gnomad FIN exome

AF:

0.572

Gnomad NFE exome

AF:

0.586

Gnomad OTH exome

AF:

0.606

GnomAD4 exome

AF:

0.573

AC:

766775

AN:

1338850

Hom.:

221362

Cov.:

AF XY:

0.572

AC XY:

384704

AN XY:

672210

show subpopulations

Gnomad4 AFR exome

AF:

0.214

Gnomad4 AMR exome

AF:

0.711

Gnomad4 ASJ exome

AF:

0.601

Gnomad4 EAS exome

AF:

0.758

Gnomad4 SAS exome

AF:

0.541

Gnomad4 FIN exome

AF:

0.559

Gnomad4 NFE exome

AF:

0.573

Gnomad4 OTH exome

AF:

0.575

GnomAD4 genome

AF:

0.496

AC:

75217

AN:

151732

Hom.:

20797

Cov.:

AF XY:

0.501

AC XY:

37186

AN XY:

74176

show subpopulations

Gnomad4 AFR

AF:

0.225

Gnomad4 AMR

AF:

0.655

Gnomad4 ASJ

AF:

0.599

Gnomad4 EAS

AF:

0.778

Gnomad4 SAS

AF:

0.565

Gnomad4 FIN

AF:

0.561

Gnomad4 NFE

AF:

0.580

Gnomad4 OTH

AF:

0.556

Alfa

AF:

0.463

Hom.:

2237

Bravo

AF:

0.495

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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 90% of patients studied by a panel of primary immunodeficiencies. Number of patients: 86. Only high quality variants are reported. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Familial cold autoinflammatory syndrome 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Familial cold autoinflammatory syndrome 3;C3553961:Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 11, 2022

- -

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

-0.87

CADD

Benign

5.6

DANN

Benign

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over