16-81854547-A-G

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.297A>G(p.Leu99Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,612,678 control chromosomes in the GnomAD database, including 74,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L99L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 5652 hom., cov: 32)

Exomes 𝑓: 0.30 ( 69113 hom. )

Consequence

PLCG2
NM_002661.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.462

Publications

16 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=-0.79).

BP6

Variant 16-81854547-A-G is Benign according to our data. Variant chr16-81854547-A-G is described in ClinVar as Benign. ClinVar VariationId is 403317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.462 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PLCG2	NM_002661.5 link	c.297A>G	p.Leu99Leu	synonymous_variant	Exon 3 of 33	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1 link	c.297A>G	p.Leu99Leu	synonymous_variant	Exon 4 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.297A>G	p.Leu99Leu	synonymous_variant	Exon 3 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.297A>G	p.Leu99Leu	synonymous_variant	Exon 4 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.297A>G	p.Leu99Leu	synonymous_variant	Exon 3 of 33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39632

AN:

152000

Hom.:

5649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.320

Gnomad EAS

AF:

0.0851

Gnomad SAS

AF:

0.281

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.280

GnomAD2 exomes

AF:

0.277

AC:

69001

AN:

249418

AF XY:

0.281

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.267

Gnomad ASJ exome

AF:

0.327

Gnomad EAS exome

AF:

0.0670

Gnomad FIN exome

AF:

0.318

Gnomad NFE exome

AF:

0.319

Gnomad OTH exome

AF:

0.292

GnomAD4 exome

AF:

0.303

AC:

442480

AN:

1460560

Hom.:

69113

Cov.:

AF XY:

0.302

AC XY:

219647

AN XY:

726622

show subpopulations

African (AFR)

AF:

0.148

AC:

4950

AN:

33466

American (AMR)

AF:

0.268

AC:

11998

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

8507

AN:

26124

East Asian (EAS)

AF:

0.0891

AC:

3535

AN:

39696

South Asian (SAS)

AF:

0.269

AC:

23236

AN:

86222

European-Finnish (FIN)

AF:

0.322

AC:

17221

AN:

53406

Middle Eastern (MID)

AF:

0.219

AC:

1264

AN:

5766

European-Non Finnish (NFE)

AF:

0.319

AC:

354609

AN:

1110820

Other (OTH)

AF:

0.284

AC:

17160

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

14460

28920

43380

57840

72300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11344

22688

34032

45376

56720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.261

AC:

39632

AN:

152118

Hom.:

5652

Cov.:

AF XY:

0.260

AC XY:

19352

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.157

AC:

6526

AN:

41506

American (AMR)

AF:

0.274

AC:

4187

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.320

AC:

1111

AN:

3468

East Asian (EAS)

AF:

0.0847

AC:

438

AN:

5170

South Asian (SAS)

AF:

0.281

AC:

1355

AN:

4826

European-Finnish (FIN)

AF:

0.321

AC:

3393

AN:

10566

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.318

AC:

21645

AN:

67972

Other (OTH)

AF:

0.276

AC:

585

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1502

3004

4507

6009

7511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.281

Hom.:

6316

Bravo

AF:

0.249

Asia WGS

AF:

0.174

AC:

606

AN:

3478

EpiCase

AF:

0.314

EpiControl

AF:

0.320

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

-0.79

CADD

Benign

0.48

(source)

DANN

Benign

0.38

PhyloP100

-0.46

Mutation Taster

=100/0

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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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