rs1071644

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.3093T>C​(p.Asn1031Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,613,270 control chromosomes in the GnomAD database, including 200,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 14051 hom., cov: 32)
Exomes 𝑓: 0.50 ( 186935 hom. )

Consequence

PLCG2
NM_002661.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.489

Publications

26 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

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=-0.52).
BP6
Variant 16-81937798-T-C is Benign according to our data. Variant chr16-81937798-T-C is described in ClinVar as [Benign]. Clinvar id is 403324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.489 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLCG2NM_002661.5 linkc.3093T>C p.Asn1031Asn synonymous_variant Exon 28 of 33 ENST00000564138.6 NP_002652.2 P16885
PLCG2NM_001425749.1 linkc.3093T>C p.Asn1031Asn synonymous_variant Exon 29 of 34 NP_001412678.1
PLCG2NM_001425750.1 linkc.3093T>C p.Asn1031Asn synonymous_variant Exon 28 of 33 NP_001412679.1
PLCG2NM_001425751.1 linkc.3093T>C p.Asn1031Asn synonymous_variant Exon 29 of 34 NP_001412680.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLCG2ENST00000564138.6 linkc.3093T>C p.Asn1031Asn synonymous_variant Exon 28 of 33 1 NM_002661.5 ENSP00000482457.1 P16885

Frequencies

GnomAD3 genomes
AF:
0.394
AC:
59920
AN:
151988
Hom.:
14054
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.141
Gnomad AMI
AF:
0.469
Gnomad AMR
AF:
0.339
Gnomad ASJ
AF:
0.554
Gnomad EAS
AF:
0.369
Gnomad SAS
AF:
0.412
Gnomad FIN
AF:
0.524
Gnomad MID
AF:
0.465
Gnomad NFE
AF:
0.531
Gnomad OTH
AF:
0.413
GnomAD2 exomes
AF:
0.445
AC:
110907
AN:
249252
AF XY:
0.458
show subpopulations
Gnomad AFR exome
AF:
0.137
Gnomad AMR exome
AF:
0.281
Gnomad ASJ exome
AF:
0.563
Gnomad EAS exome
AF:
0.354
Gnomad FIN exome
AF:
0.521
Gnomad NFE exome
AF:
0.528
Gnomad OTH exome
AF:
0.470
GnomAD4 exome
AF:
0.499
AC:
728819
AN:
1461164
Hom.:
186935
Cov.:
36
AF XY:
0.499
AC XY:
363069
AN XY:
726914
show subpopulations
African (AFR)
AF:
0.129
AC:
4305
AN:
33474
American (AMR)
AF:
0.289
AC:
12907
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
0.564
AC:
14728
AN:
26128
East Asian (EAS)
AF:
0.388
AC:
15417
AN:
39690
South Asian (SAS)
AF:
0.432
AC:
37268
AN:
86218
European-Finnish (FIN)
AF:
0.517
AC:
27579
AN:
53394
Middle Eastern (MID)
AF:
0.488
AC:
2812
AN:
5768
European-Non Finnish (NFE)
AF:
0.526
AC:
585121
AN:
1111418
Other (OTH)
AF:
0.475
AC:
28682
AN:
60370
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
18205
36410
54616
72821
91026
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
16446
32892
49338
65784
82230
<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:
0.394
AC:
59912
AN:
152106
Hom.:
14051
Cov.:
32
AF XY:
0.392
AC XY:
29119
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.141
AC:
5851
AN:
41508
American (AMR)
AF:
0.338
AC:
5175
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.554
AC:
1925
AN:
3472
East Asian (EAS)
AF:
0.369
AC:
1906
AN:
5160
South Asian (SAS)
AF:
0.413
AC:
1990
AN:
4820
European-Finnish (FIN)
AF:
0.524
AC:
5534
AN:
10566
Middle Eastern (MID)
AF:
0.452
AC:
133
AN:
294
European-Non Finnish (NFE)
AF:
0.531
AC:
36103
AN:
67968
Other (OTH)
AF:
0.410
AC:
867
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
1687
3375
5062
6750
8437
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
572
1144
1716
2288
2860
<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:
0.465
Hom.:
41773
Bravo
AF:
0.372
Asia WGS
AF:
0.327
AC:
1136
AN:
3478
EpiCase
AF:
0.528
EpiControl
AF:
0.530

ClinVar

Significance: Benign
Submissions summary: Benign:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
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

- -

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 -

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 58% of patients studied by a panel of primary immunodeficiencies. Number of patients: 56. Only high quality variants are reported. -

not provided Benign:2Other:1
-
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

- -

-
GenomeConnect, ClinGen
Significance:not provided
Review Status:no classification provided
Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Familial cold autoinflammatory syndrome 3 Benign:2
Oct 25, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
-0.52
CADD
Benign
1.1
DANN
Benign
0.57
PhyloP100
-0.49
Mutation Taster
=98/2
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1071644; hg19: chr16-81971403; COSMIC: COSV63872588; COSMIC: COSV63872588; API