16-81921184-C-G

Variant summary

Our verdict is Benign. Variant got -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

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.948
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 403323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81921184-C-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLCG2NM_002661.5 linkc.2236-14C>G intron_variant Intron 20 of 32 ENST00000564138.6 NP_002652.2 P16885
PLCG2NM_001425749.1 linkc.2236-14C>G intron_variant Intron 21 of 33 NP_001412678.1
PLCG2NM_001425750.1 linkc.2236-14C>G intron_variant Intron 20 of 32 NP_001412679.1
PLCG2NM_001425751.1 linkc.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
PLCG2ENST00000564138.6 linkc.2236-14C>G intron_variant Intron 20 of 32 1 NM_002661.5 ENSP00000482457.1 P16885

Frequencies

GnomAD3 genomes
AF:
0.496
AC:
75191
AN:
151620
Hom.:
20800
Cov.:
31
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
GnomAD3 exomes
AF:
0.595
AC:
141304
AN:
237632
Hom.:
42541
AF XY:
0.594
AC XY:
76689
AN XY:
129028
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 SAS exome
AF:
0.557
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.:
21
AF XY:
0.572
AC XY:
384704
AN XY:
672210
show subpopulations
Gnomad4 AFR exome
AF:
0.214
Gnomad4 AMR exome
AF:
0.711
Gnomad4 ASJ exome
AF:
0.601
Gnomad4 EAS exome
AF:
0.758
Gnomad4 SAS exome
AF:
0.541
Gnomad4 FIN exome
AF:
0.559
Gnomad4 NFE exome
AF:
0.573
Gnomad4 OTH exome
AF:
0.575
GnomAD4 genome
AF:
0.496
AC:
75217
AN:
151732
Hom.:
20797
Cov.:
31
AF XY:
0.501
AC XY:
37186
AN XY:
74176
show subpopulations
Gnomad4 AFR
AF:
0.225
Gnomad4 AMR
AF:
0.655
Gnomad4 ASJ
AF:
0.599
Gnomad4 EAS
AF:
0.778
Gnomad4 SAS
AF:
0.565
Gnomad4 FIN
AF:
0.561
Gnomad4 NFE
AF:
0.580
Gnomad4 OTH
AF:
0.556
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

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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

- -

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
DANN
Benign
0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12446127; hg19: chr16-81954789; COSMIC: COSV63875032; COSMIC: COSV63875032; API