1-247425556-C-A
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BA1
The NM_001243133.2(NLRP3):c.2107C>A(p.Gln703Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,611,524 control chromosomes in the GnomAD database, including 1,736 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q703H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001243133.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NLRP3 | NM_001243133.2 | c.2107C>A | p.Gln703Lys | missense_variant | Exon 4 of 10 | ENST00000336119.8 | NP_001230062.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NLRP3 | ENST00000336119.8 | c.2107C>A | p.Gln703Lys | missense_variant | Exon 4 of 10 | 1 | NM_001243133.2 | ENSP00000337383.4 |
Frequencies
GnomAD3 genomes AF: 0.0328 AC: 4990AN: 152126Hom.: 126 Cov.: 32
GnomAD3 exomes AF: 0.0391 AC: 9757AN: 249326Hom.: 238 AF XY: 0.0412 AC XY: 5564AN XY: 135008
GnomAD4 exome AF: 0.0444 AC: 64760AN: 1459280Hom.: 1610 Cov.: 37 AF XY: 0.0444 AC XY: 32258AN XY: 726112
GnomAD4 genome AF: 0.0328 AC: 4994AN: 152244Hom.: 126 Cov.: 32 AF XY: 0.0325 AC XY: 2417AN XY: 74424
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
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In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32477355, 26178285, 32199921, 22843550, 30245029, 29148409, 28638818, 28692792, 29977033, 29265930, 30140708, 29610014, 27576327, 29770580, 23215645, 29850521, 29230505, 22128899, 17509468, 22529966, 28028683, 26020059, 27036377, 27943647, 26848126, 27884173, 22403613, 22995991, 20182451, 25596455, 22935299, 18311798, 21245836, 19319132, 20981092, 29097263, 29500522, 30447690, 30536174) -
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PS3, BS1, BP4 -
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not specified Benign:6
The p.Gln705Lys variant in NLRP3 is classified as benign because it has been identified in 3.8% (10781/280716) of total chromosomes, including 266 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been reported in association with autoimmune or inflammatory conditions, several studies have shown equal frequency in cases and ethnically matched controls (Jenko 2016, Lidar 2017, Naselli 2016, Yang 2017). ACMG/AMP criteria: BA1. -
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Familial cold autoinflammatory syndrome 1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Cryopyrin associated periodic syndrome Benign:1
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Focal segmental glomerulosclerosis Benign:1
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Familial amyloid nephropathy with urticaria AND deafness Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Autoinflammatory syndrome Benign:1
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Chronic infantile neurological, cutaneous and articular syndrome Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at