rs781621510
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002661.5(PLCG2):c.1934C>T(p.Pro645Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,606,982 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
PLCG2
NM_002661.5 missense, splice_region
NM_002661.5 missense, splice_region
Scores
8
8
Splicing: ADA: 0.7354
2
Clinical Significance
Conservation
PhyloP100: 3.42
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 Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAdExome4 at 16 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLCG2 | NM_002661.5 | c.1934C>T | p.Pro645Leu | missense_variant, splice_region_variant | 18/33 | ENST00000564138.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLCG2 | ENST00000564138.6 | c.1934C>T | p.Pro645Leu | missense_variant, splice_region_variant | 18/33 | 1 | NM_002661.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000123 AC: 3AN: 243258Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132686
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1454778Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 724128
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
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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
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 07, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 645 of the PLCG2 protein (p.Pro645Leu). This variant is present in population databases (rs781621510, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with PLCG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 540094). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;T
Polyphen
B;.
Vest4
MutPred
Loss of disorder (P = 0.0218);Loss of disorder (P = 0.0218);
MVP
MPC
0.31
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at