1-247449260-T-C

Variant names:

• chr1-247449260-T-C
• rs10925027
• NM_001004492.2:c.*1769A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001004492.2(OR2B11):​c.*1769A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 152,100 control chromosomes in the GnomAD database, including 25,474 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (25463 hom., cov: 33)
  • Exomes 𝑓: 0.57 (11 hom.)
• Consequence: OR2B11 NM_001004492.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 24 publications found

Genes affected

OR2B11 (HGNC:31249): (olfactory receptor family 2 subfamily B member 11) Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms. [provided by RefSeq, Jul 2008]

NLRP3 (HGNC:16400): (NLR family pyrin domain containing 3) This gene encodes a pyrin-like protein containing a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NLRP3 inflammasome complex. This complex functions as an upstream activator of NF-kappaB signaling, and it plays a role in the regulation of inflammation, the immune response, and apoptosis. The SARS-CoV 3a protein, a transmembrane pore-forming viroporin, has been shown to activate the NLRP3 inflammasome via the formation of ion channels in macrophages. Mutations in this gene are associated with familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), keratoendotheliitis fugax hereditarian, and deafness, autosomal dominant 34, with or without inflammation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Alternative 5' UTR structures are suggested by available data; however, insufficient evidence is available to determine if all of the represented 5' UTR splice patterns are biologically valid. [provided by RefSeq, Aug 2020]

NLRP3 Gene-Disease associations (from GenCC):

• CINCA syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cryopyrin-associated periodic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• familial cold autoinflammatory syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• familial cold autoinflammatory syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Muckle-Wells syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• keratitis fugax hereditaria

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2B11	NM_001004492.2	c.*1769A>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000641149.2	NP_001004492.1
OR2B11	NR_169840.1	n.3377A>G		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2B11	ENST00000641149.2	c.*1769A>G		3_prime_UTR_variant	Exon 2 of 2		NM_001004492.2	ENSP00000492892.1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87197 AN: 151922 Hom.: 25452 Cov.: 33

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.582

GnomAD4 exome AF: 0.567 AC: 34 AN: 60 Hom.: 11 Cov.: 0 AF XY: 0.667 AC XY: 24 AN XY: 36

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.571 AC: 32 AN: 56

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.574 AC: 87243 AN: 152040 Hom.: 25463 Cov.: 33 AF XY: 0.571 AC XY: 42450 AN XY: 74310

African (AFR) AF: 0.542 AC: 22473 AN: 41452

American (AMR) AF: 0.498 AC: 7605 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2721 AN: 3468

East Asian (EAS) AF: 0.455 AC: 2348 AN: 5162

South Asian (SAS) AF: 0.536 AC: 2585 AN: 4826

European-Finnish (FIN) AF: 0.608 AC: 6423 AN: 10570

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 40979 AN: 67976

Other (OTH) AF: 0.577 AC: 1220 AN: 2114

Alfa AF: 0.594 Hom.: 90529

Bravo AF: 0.567

Asia WGS AF: 0.479 AC: 1664 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.4
DANN	Benign	0.66
PhyloP100		-0.12

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10925027; hg19: chr1-247612562;