16-81786051-C-T

Variant summary

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

The NM_002661.5(PLCG2):​c.62C>T​(p.Ala21Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)

Consequence

PLCG2
NM_002661.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.88
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=0.2382609).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLCG2NM_002661.5 linkc.62C>T p.Ala21Val missense_variant Exon 2 of 33 ENST00000564138.6 NP_002652.2 P16885
PLCG2NM_001425749.1 linkc.62C>T p.Ala21Val missense_variant Exon 3 of 34 NP_001412678.1
PLCG2NM_001425750.1 linkc.62C>T p.Ala21Val missense_variant Exon 2 of 33 NP_001412679.1
PLCG2NM_001425751.1 linkc.62C>T p.Ala21Val 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.62C>T p.Ala21Val missense_variant Exon 2 of 33 1 NM_002661.5 ENSP00000482457.1 P16885

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation Uncertain:1
-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense c.62C>Tp.Ala21Val variant in PLCG2 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Ala21Val variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Ala21Val in PLCG2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 21 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.082
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;T;.
Eigen
Benign
-0.048
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.24
T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
1.4
.;L;.
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.78
N;.;N
REVEL
Benign
0.047
Sift
Benign
0.39
T;.;T
Sift4G
Benign
0.23
T;T;T
Polyphen
0.020
.;B;.
Vest4
0.35, 0.32
MutPred
0.40
Loss of ubiquitination at K19 (P = 0.063);Loss of ubiquitination at K19 (P = 0.063);Loss of ubiquitination at K19 (P = 0.063);
MVP
0.42
MPC
0.071
ClinPred
0.74
D
GERP RS
5.1
Varity_R
0.18
gMVP
0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-81819656; API