16-81921184-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

10 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 -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 Benign/Likely_benign. ClinVar VariationId is 403323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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
PLCG2	NM_002661.5 link	c.2236-14C>G	intron_variant	Intron 20 of 32	ENST00000564138.6	NP_002652.2
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

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

GnomAD2 exomes

AF:

0.595

AC:

141304

AN:

237632

AF XY:

0.594

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 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

African (AFR)

AF:

0.214

AC:

6735

AN:

31532

American (AMR)

AF:

0.711

AC:

31322

AN:

44070

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

15122

AN:

25162

East Asian (EAS)

AF:

0.758

AC:

29218

AN:

38526

South Asian (SAS)

AF:

0.541

AC:

45095

AN:

83350

European-Finnish (FIN)

AF:

0.559

AC:

29454

AN:

52728

Middle Eastern (MID)

AF:

0.604

AC:

3347

AN:

5544

European-Non Finnish (NFE)

AF:

0.573

AC:

574208

AN:

1001766

Other (OTH)

AF:

0.575

AC:

32274

AN:

56172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

13884

27768

41652

55536

69420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15386

30772

46158

61544

76930

<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:

0.496

AC:

75217

AN:

151732

Hom.:

20797

Cov.:

AF XY:

0.501

AC XY:

37186

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.225

AC:

9312

AN:

41296

American (AMR)

AF:

0.655

AC:

9990

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.599

AC:

2076

AN:

3466

East Asian (EAS)

AF:

0.778

AC:

4020

AN:

5166

South Asian (SAS)

AF:

0.565

AC:

2710

AN:

4796

European-Finnish (FIN)

AF:

0.561

AC:

5914

AN:

10550

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.580

AC:

39411

AN:

67894

Other (OTH)

AF:

0.556

AC:

1168

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1741

3481

5222

6962

8703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

666

1332

1998

2664

3330

<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:

0.463

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

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 -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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 90% of patients studied by a panel of primary immunodeficiencies. Number of patients: 86. Only high quality variants are reported. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 14, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cold autoinflammatory syndrome 3

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Mar 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

Benign:1

Oct 25, 2021

Genome-Nilou Lab

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

-0.87

CADD

Benign

5.6

(source)

DANN

Benign

0.41

PhyloP100

-0.95

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