19-53793706-T-C

Variant names:

• chr19-53793706-T-C
• rs540448720
• ENST00000391773.8:c.*343A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001277129.1(NLRP12):​c.*343A>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 0.00000769 in 130,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000077 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NLRP12 NM_001277129.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.382
• Publications: 0 publications found

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]

NLRP12 Gene-Disease associations (from GenCC):

• familial cold autoinflammatory syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277129.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	NM_001277129.1		c.*343A>G		3_prime_UTR	Exon 9 of 9	NP_001264058.1	P59046-6
	NLRP12	NM_144687.4	MANE Select	c.*343A>G		downstream_gene	N/A	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.*343A>G		downstream_gene	N/A	NP_001264055.1	P59046-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000391773.8	TSL:1	c.*343A>G		3_prime_UTR	Exon 10 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.*343A>G		downstream_gene	N/A	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000345770.9	TSL:1	c.*343A>G		downstream_gene	N/A	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.00000769 AC: 1 AN: 130096 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000166

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000479 AC: 1 AN: 208918 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 113204

African (AFR) AF: 0.00 AC: 0 AN: 6150

American (AMR) AF: 0.00 AC: 0 AN: 11130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5194

East Asian (EAS) AF: 0.00 AC: 0 AN: 9886

South Asian (SAS) AF: 0.00 AC: 0 AN: 37312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 764

European-Non Finnish (NFE) AF: 0.00000842 AC: 1 AN: 118800

Other (OTH) AF: 0.00 AC: 0 AN: 10684

GnomAD4 genome AF: 0.00000769 AC: 1 AN: 130096 Hom.: 0 Cov.: 27 AF XY: 0.0000159 AC XY: 1 AN XY: 62848

African (AFR) AF: 0.00 AC: 0 AN: 33812

American (AMR) AF: 0.00 AC: 0 AN: 12726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3142

East Asian (EAS) AF: 0.00 AC: 0 AN: 4924

South Asian (SAS) AF: 0.00 AC: 0 AN: 4032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000166 AC: 1 AN: 60346

Other (OTH) AF: 0.00 AC: 0 AN: 1796

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cold autoinflammatory syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.3
DANN	Benign	0.65
PhyloP100		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs540448720; hg19: chr19-54296960;