NM_002661.5:c.35A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002661.5(PLCG2):ā€‹c.35A>Gā€‹(p.Glu12Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLCG2NM_002661.5 linkc.35A>G p.Glu12Gly missense_variant Exon 2 of 33 ENST00000564138.6 NP_002652.2 P16885
PLCG2NM_001425749.1 linkc.35A>G p.Glu12Gly missense_variant Exon 3 of 34 NP_001412678.1
PLCG2NM_001425750.1 linkc.35A>G p.Glu12Gly missense_variant Exon 2 of 33 NP_001412679.1
PLCG2NM_001425751.1 linkc.35A>G p.Glu12Gly missense_variant Exon 3 of 34 NP_001412680.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLCG2ENST00000564138.6 linkc.35A>G p.Glu12Gly missense_variant Exon 2 of 33 1 NM_002661.5 ENSP00000482457.1 P16885

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461870
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 3 Uncertain:1
Jun 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 12 of the PLCG2 protein (p.Glu12Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PLCG2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.073
D
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.37
T;D;.
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.79
T;T;T
M_CAP
Benign
0.074
D
MetaRNN
Uncertain
0.65
D;D;D
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
1.2
.;L;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-3.0
D;.;N
REVEL
Uncertain
0.44
Sift
Uncertain
0.0060
D;.;D
Sift4G
Uncertain
0.011
D;D;D
Polyphen
0.95
.;P;.
Vest4
0.69, 0.66
MutPred
0.52
Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP
0.65
MPC
0.38
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.29
gMVP
0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-81819629; API