chr16-81910724-C-T
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_002661.5(PLCG2):c.1934+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,606,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
PLCG2
NM_002661.5 splice_donor_region, intron
NM_002661.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0002997
2
Clinical Significance
Conservation
PhyloP100: -4.53
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 -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000105 (16/152306) while in subpopulation NFE AF= 0.000191 (13/68028). AF 95% confidence interval is 0.000112. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 16 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLCG2 | NM_002661.5 | c.1934+4C>T | splice_donor_region_variant, intron_variant | ENST00000564138.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLCG2 | ENST00000564138.6 | c.1934+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_002661.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000536 AC: 13AN: 242718Hom.: 0 AF XY: 0.0000453 AC XY: 6AN XY: 132442
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GnomAD4 exome AF: 0.000124 AC: 180AN: 1454022Hom.: 0 Cov.: 32 AF XY: 0.000117 AC XY: 85AN XY: 723806
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GnomAD4 genome AF: 0.000105 AC: 16AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74480
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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 | Nov 27, 2023 | This sequence change falls in intron 18 of the PLCG2 gene. It does not directly change the encoded amino acid sequence of the PLCG2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs370532346, gnomAD 0.01%). 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: 575238). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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