19-53809584-T-TA
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_144687.4(NLRP12):c.2072+2_2072+3insT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,604,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: đť‘“ 0.00040 ( 0 hom., cov: 32)
Exomes đť‘“: 0.000071 ( 0 hom. )
Consequence
NLRP12
NM_144687.4 splice_region, intron
NM_144687.4 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.31
Genes affected
NLRP12 (HGNC:22938): (NLR family pyrin domain containing 12) This gene encodes a member of the CATERPILLER family of cytoplasmic proteins. The encoded protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain, and a C-terminus leucine-rich repeat region, functions as an attenuating factor of inflammation by suppressing inflammatory responses in activated monocytes. Mutations in this gene cause familial cold autoinflammatory syndrome type 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS2
?
High AC in GnomAd at 53 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLRP12 | NM_144687.4 | c.2072+2_2072+3insT | splice_region_variant, intron_variant | ENST00000324134.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRP12 | ENST00000324134.11 | c.2072+2_2072+3insT | splice_region_variant, intron_variant | 1 | NM_144687.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000355 AC: 53AN: 149280Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000109 AC: 27AN: 247892Hom.: 0 AF XY: 0.0000891 AC XY: 12AN XY: 134654
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GnomAD4 exome AF: 0.0000715 AC: 104AN: 1455266Hom.: 0 Cov.: 40 AF XY: 0.0000705 AC XY: 51AN XY: 723896
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GnomAD4 genome ? AF: 0.000402 AC: 60AN: 149332Hom.: 0 Cov.: 32 AF XY: 0.000441 AC XY: 32AN XY: 72556
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 30, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | NLRP12: PP3, PS3:Supporting, BS1 - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Familial cold autoinflammatory syndrome 2 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18230725). ClinVar contains an entry for this variant (Variation ID: 1597). This variant is also known as NALP12 c.2072+3insT. This variant has been observed in individual(s) with clinical features of familial cold autoinflammatory syndrome (PMID: 18230725, 31820221). This variant is present in population databases (rs104895565, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change falls in intron 3 of the NLRP12 gene. It does not directly change the encoded amino acid sequence of the NLRP12 protein. It affects a nucleotide within the consensus splice site. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 05, 2008 | - - |
Autoinflammatory syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2018 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -33
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at