NM_002661.5:c.1149C>T

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.1149C>T(p.Asp383Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,613,436 control chromosomes in the GnomAD database, including 124,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 10718 hom., cov: 31)

Exomes 𝑓: 0.38 ( 113422 hom. )

Consequence

PLCG2
NM_002661.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.31

Publications

23 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=-0.71).

BP6

Variant 16-81895883-C-T is Benign according to our data. Variant chr16-81895883-C-T is described in ClinVar as Benign. ClinVar VariationId is 403320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.1149C>T	p.Asp383Asp	synonymous_variant	Exon 13 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.1149C>T	p.Asp383Asp	synonymous_variant	Exon 14 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.1149C>T	p.Asp383Asp	synonymous_variant	Exon 13 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.1149C>T	p.Asp383Asp	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.1149C>T	p.Asp383Asp	synonymous_variant	Exon 13 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.344

AC:

52187

AN:

151818

Hom.:

10711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.340

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.348

Gnomad EAS

AF:

0.719

Gnomad SAS

AF:

0.399

Gnomad FIN

AF:

0.443

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.374

Gnomad OTH

AF:

0.377

GnomAD2 exomes

AF:

0.429

AC:

107092

AN:

249514

AF XY:

0.422

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.659

Gnomad ASJ exome

AF:

0.344

Gnomad EAS exome

AF:

0.709

Gnomad FIN exome

AF:

0.429

Gnomad NFE exome

AF:

0.375

Gnomad OTH exome

AF:

0.416

GnomAD4 exome

AF:

0.384

AC:

560548

AN:

1461500

Hom.:

113422

Cov.:

AF XY:

0.383

AC XY:

278242

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.131

AC:

4385

AN:

33480

American (AMR)

AF:

0.641

AC:

28689

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

8941

AN:

26130

East Asian (EAS)

AF:

0.702

AC:

27854

AN:

39694

South Asian (SAS)

AF:

0.385

AC:

33172

AN:

86246

European-Finnish (FIN)

AF:

0.434

AC:

23179

AN:

53402

Middle Eastern (MID)

AF:

0.350

AC:

2020

AN:

5764

European-Non Finnish (NFE)

AF:

0.368

AC:

409224

AN:

1111674

Other (OTH)

AF:

0.382

AC:

23084

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

17494

34988

52482

69976

87470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13072

26144

39216

52288

65360

<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:

0.344

AC:

52202

AN:

151936

Hom.:

10718

Cov.:

AF XY:

0.356

AC XY:

26401

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.145

AC:

5997

AN:

41476

American (AMR)

AF:

0.531

AC:

8108

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

1208

AN:

3468

East Asian (EAS)

AF:

0.720

AC:

3694

AN:

5132

South Asian (SAS)

AF:

0.399

AC:

1921

AN:

4816

European-Finnish (FIN)

AF:

0.443

AC:

4675

AN:

10542

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.374

AC:

25393

AN:

67920

Other (OTH)

AF:

0.376

AC:

795

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1606

3211

4817

6422

8028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.347

Hom.:

4932

Bravo

AF:

0.342

Asia WGS

AF:

0.534

AC:

1855

AN:

3478

EpiCase

AF:

0.364

EpiControl

AF:

0.368

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 14, 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 82% of patients studied by a panel of primary immunodeficiencies. Number of patients: 79. Only high quality variants are reported. -

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

- -

not provided

Benign:3

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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

-0.71

CADD

Benign

0.49

(source)

DANN

Benign

0.92

PhyloP100

-1.3

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