16-81786050-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002661.5(PLCG2):​c.61G>A​(p.Ala21Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13564679).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLCG2NM_002661.5 linkc.61G>A p.Ala21Thr missense_variant Exon 2 of 33 ENST00000564138.6 NP_002652.2 P16885
PLCG2NM_001425749.1 linkc.61G>A p.Ala21Thr missense_variant Exon 3 of 34 NP_001412678.1
PLCG2NM_001425750.1 linkc.61G>A p.Ala21Thr missense_variant Exon 2 of 33 NP_001412679.1
PLCG2NM_001425751.1 linkc.61G>A p.Ala21Thr 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.61G>A p.Ala21Thr missense_variant Exon 2 of 33 1 NM_002661.5 ENSP00000482457.1 P16885

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461874
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727240
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
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
Apr 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 21 of the PLCG2 protein (p.Ala21Thr). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
0.078
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.25
T;T;.
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.71
T;T;T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.14
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.060
.;N;.
PrimateAI
Benign
0.41
T
PROVEAN
Benign
0.060
N;.;N
REVEL
Benign
0.059
Sift
Benign
0.71
T;.;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
.;B;.
Vest4
0.071, 0.076
MutPred
0.39
Gain of ubiquitination at K19 (P = 0.0725);Gain of ubiquitination at K19 (P = 0.0725);Gain of ubiquitination at K19 (P = 0.0725);
MVP
0.51
MPC
0.061
ClinPred
0.59
D
GERP RS
2.9
Varity_R
0.047
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1248111391; hg19: chr16-81819655; COSMIC: COSV63868860; API