rs13333716

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.194

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
familial cold autoinflammatory syndrome 3
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

PLCG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.1188C>G	p.Thr396Thr	synonymous_variant	Exon 13 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.1188C>G	p.Thr396Thr	synonymous_variant	Exon 14 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.1188C>G	p.Thr396Thr	synonymous_variant	Exon 13 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.1188C>G	p.Thr396Thr	synonymous_variant	Exon 14 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.1188C>G	p.Thr396Thr	synonymous_variant	Exon 13 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.0651

AC:

9901

AN:

152010

Hom.:

372

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0525

AC:

13089

AN:

249510

AF XY:

0.0518

show subpopulations

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 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.:

AF XY:

0.0684

AC XY:

49743

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0824

AC:

2758

AN:

33478

American (AMR)

AF:

0.0364

AC:

1628

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

1017

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0274

AC:

2364

AN:

86254

European-Finnish (FIN)

AF:

0.0514

AC:

2746

AN:

53406

Middle Eastern (MID)

AF:

0.0378

AC:

218

AN:

5768

European-Non Finnish (NFE)

AF:

0.0788

AC:

87601

AN:

1111938

Other (OTH)

AF:

0.0661

AC:

3993

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

4806

9613

14419

19226

24032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0652

AC:

9920

AN:

152128

Hom.:

375

Cov.:

AF XY:

0.0629

AC XY:

4674

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0812

AC:

3367

AN:

41470

American (AMR)

AF:

0.0442

AC:

675

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0392

AC:

136

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0256

AC:

123

AN:

4808

European-Finnish (FIN)

AF:

0.0479

AC:

508

AN:

10600

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0724

AC:

4923

AN:

68012

Other (OTH)

AF:

0.0479

AC:

101

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

465

930

1395

1860

2325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0673

Hom.:

134

Bravo

AF:

0.0661

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0715

EpiControl

AF:

0.0722

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cold autoinflammatory syndrome 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.5

(source)

DANN

Benign

0.54

PhyloP100

-0.19

Mutation Taster

=73/27

polymorphism (auto)

(source)

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

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rs13333716

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over