VCV000987914.10 - ClinVar

NM_144687.4(NLRP12):c.1952C>A (p.Ser651Ter)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

2 out of 2 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_144687.4(NLRP12):c.1952C>A (p.Ser651Ter)

Variation ID: 987914 Accession: VCV000987914.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.42 19: 53809707 (GRCh38) [ NCBI UCSC ] 19: 54312961 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 7, 2020	Apr 13, 2025	Dec 16, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_144687.4:c.1952C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_653288.1:p.Ser651Ter	nonsense
NM_001277126.2:c.1952C>A	NP_001264055.1:p.Ser651Ter	nonsense
NM_001277129.1:c.1952C>A	NP_001264058.1:p.Ser651Ter	nonsense
NC_000019.10:g.53809707G>T
NC_000019.9:g.54312961G>T
NG_008651.2:g.19688C>A
LRG_181:g.19688C>A
LRG_181t1:c.1952C>A	LRG_181p1:p.Ser651Ter
LRG_181t2:c.1952C>A	LRG_181p2:p.Ser651Ter

... more HGVS ... less HGVS

Protein change

S651*

Other names

Canonical SPDI

NC_000019.10:53809706:G:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA9639309 dbSNP: rs781361326 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NLRP12		-	-	GRCh38 GRCh37	1486	1517

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Familial cold autoinflammatory syndrome 2	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Dec 16, 2020	RCV001269323.14

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Dec 16, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Familial cold autoinflammatory syndrome 2	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002050258.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: show The NLRP12 c.1952C>A; p.Ser651Ter variant (rs781361326), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found on only four chromosomes (4/251382 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. While loss-of-function variants in NLRP12 have been reported in individuals affected with autoinflammatory disease or periodic fever syndromes (Hua 2019, Jeru 2008, Kostik 2018, Xia 2016), the mechanism by which such variants cause disease remains uncertain (Tuncer 2014). Due to limited information, the clinical significance of the p.Ser651Ter variant is uncertain at this time. References: Hua Y et al. Phenotypes and genotypes of Chinese adult patients with systemic autoinflammatory diseases. Semin Arthritis Rheum. 2019 Dec;49(3):446-452. Jeru I et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9. Kostik MM et al. Multigene sequencing reveals heterogeneity of NLRP12-related autoinflammatory disorders. Rheumatol Int. 2018 May;38(5):887-893. Tuncer S et al. The multifaceted nature of NLRP12. J Leukoc Biol. 2014 Dec;96(6):991-1000. Xia X et al. Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing. PLoS One. 2016 Jun 17;11(6):e0156981. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 04, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial cold autoinflammatory syndrome 2	Dubai Health Genomic Medicine Center, Dubai Health Accession: SCV001448259.2 First in ClinVar: Dec 07, 2020 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Sex: female

Comment:

The NLRP12 c.1952C>A; p.Ser651Ter variant (rs781361326), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found on only four chromosomes (4/251382 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. While loss-of-function variants in NLRP12 have been reported in individuals affected with autoinflammatory disease or periodic fever syndromes (Hua 2019, Jeru 2008, Kostik 2018, Xia 2016), the mechanism by which such variants cause disease remains uncertain (Tuncer 2014). Due to limited information, the clinical significance of the p.Ser651Ter variant is uncertain at this time. References: Hua Y et al. Phenotypes and genotypes of Chinese adult patients with systemic autoinflammatory diseases. Semin Arthritis Rheum. 2019 Dec;49(3):446-452. Jeru I et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9. Kostik MM et al. Multigene sequencing reveals heterogeneity of NLRP12-related autoinflammatory disorders. Rheumatol Int. 2018 May;38(5):887-893. Tuncer S et al. The multifaceted nature of NLRP12. J Leukoc Biol. 2014 Dec;96(6):991-1000. Xia X et al. Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing. PLoS One. 2016 Jun 17;11(6):e0156981.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs781361326 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 01, 2025