rs61749044
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002661.5(PLCG2):c.82A>T(p.Met28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,614,186 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.010 ( 16 hom., cov: 32)
Exomes 𝑓: 0.015 ( 218 hom. )
Consequence
PLCG2
NM_002661.5 missense
NM_002661.5 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 8.94
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 (MetaRNN=0.0093021095).
BP6
Variant 16-81786071-A-T is Benign according to our data. Variant chr16-81786071-A-T is described in ClinVar as [Benign]. Clinvar id is 440153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81786071-A-T is described in Lovd as [Likely_benign]. Variant chr16-81786071-A-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.01 (1525/152338) while in subpopulation SAS AF= 0.017 (82/4826). AF 95% confidence interval is 0.015. There are 16 homozygotes in gnomad4. There are 728 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1525 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLCG2 | NM_002661.5 | c.82A>T | p.Met28Leu | missense_variant | 2/33 | ENST00000564138.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLCG2 | ENST00000564138.6 | c.82A>T | p.Met28Leu | missense_variant | 2/33 | 1 | NM_002661.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0100 AC: 1525AN: 152220Hom.: 16 Cov.: 32
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GnomAD3 exomes AF: 0.0108 AC: 2693AN: 249582Hom.: 20 AF XY: 0.0117 AC XY: 1590AN XY: 135404
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GnomAD4 exome AF: 0.0153 AC: 22358AN: 1461848Hom.: 218 Cov.: 31 AF XY: 0.0152 AC XY: 11080AN XY: 727228
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GnomAD4 genome AF: 0.0100 AC: 1525AN: 152338Hom.: 16 Cov.: 32 AF XY: 0.00977 AC XY: 728AN XY: 74500
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | PLCG2: BS1, BS2 - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Familial cold autoinflammatory syndrome 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Benign
Sift
Benign
T;.;T
Sift4G
Benign
T;T;T
Polyphen
0.85
.;P;.
Vest4
0.38, 0.24
MutPred
Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MPC
0.37
ClinPred
T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at