rs199881207
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_144687.4(NLRP12):c.1054C>T(p.Arg352Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_144687.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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NLRP12 | ENST00000324134.11 | c.1054C>T | p.Arg352Cys | missense_variant | Exon 3 of 10 | 1 | NM_144687.4 | ENSP00000319377.6 | ||
NLRP12 | ENST00000345770.9 | c.1054C>T | p.Arg352Cys | missense_variant | Exon 3 of 9 | 1 | ENSP00000341428.5 | |||
NLRP12 | ENST00000391772.1 | c.1054C>T | p.Arg352Cys | missense_variant | Exon 3 of 7 | 1 | ENSP00000375652.1 |
Frequencies
GnomAD3 genomes AF: 0.000230 AC: 35AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000378 AC: 95AN: 251250Hom.: 0 AF XY: 0.000479 AC XY: 65AN XY: 135816
GnomAD4 exome AF: 0.000287 AC: 419AN: 1461852Hom.: 1 Cov.: 40 AF XY: 0.000326 AC XY: 237AN XY: 727222
GnomAD4 genome AF: 0.000230 AC: 35AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74418
ClinVar
Submissions by phenotype
Familial cold autoinflammatory syndrome 2 Pathogenic:1Uncertain:2Benign:2
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The NLRP12 c.1054C>T; p.Arg352Cys variant (rs199881207) is published in the medical literature in 3 unrelated individuals with periodic fever or autoimmune disease without urticaria (Jeru 2011, Rusmini 2016). The variant is reported in the ClinVar database (Variation ID: 523654) and in the general population with an allele frequency of 0.04% (102/282638 alleles) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Experiments in cell culture show this variant did not affect the NF-KB inhibitory activity, but did enhance processing of caspase-1 compared to wild type (Jeru 2011); these authors suggested that this variant may act in a gain of function mechanism, in contrast to NLRP12 nonsense variants that appear to have a loss of function. However, given the limited clinical and functional data, the significance of the variant is uncertain at this time. References: Jeru I et al. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum. 2011 May;63(5):1459-64. Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7. -
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not provided Uncertain:3Benign:1
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NLRP12: BP4 -
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Autoinflammatory syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at