rs977656147
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2
The NM_002661.5(PLCG2):c.3004C>A(p.Leu1002Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1002F) has been classified as Uncertain significance.
Frequency
Consequence
NM_002661.5 missense
Scores
Clinical Significance
Conservation
Publications
- autoinflammation-PLCG2-associated antibody deficiency-immune dysregulationInheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
- familial cold autoinflammatory syndrome 3Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
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ACMG classification
Our verdict: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLCG2 | NM_002661.5 | c.3004C>A | p.Leu1002Ile | missense_variant | Exon 27 of 33 | ENST00000564138.6 | NP_002652.2 | |
PLCG2 | NM_001425749.1 | c.3004C>A | p.Leu1002Ile | missense_variant | Exon 28 of 34 | NP_001412678.1 | ||
PLCG2 | NM_001425750.1 | c.3004C>A | p.Leu1002Ile | missense_variant | Exon 27 of 33 | NP_001412679.1 | ||
PLCG2 | NM_001425751.1 | c.3004C>A | p.Leu1002Ile | missense_variant | Exon 28 of 34 | NP_001412680.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000401 AC: 1AN: 249510 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727238 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74372 show subpopulations
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.3004C>A (p.L1002I) alteration is located in exon 27 (coding exon 26) of the PLCG2 gene. This alteration results from a C to A substitution at nucleotide position 3004, causing the leucine (L) at amino acid position 1002 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Familial cold autoinflammatory syndrome 3 Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1002 of the PLCG2 protein (p.Leu1002Ile). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PLCG2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at