chr19-53807707-G-C

Variant names:

• chr19-53807707-G-C
• rs2866112
• ENST00000492915.1:n.999C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000492915.1(NLRP12):​n.999C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 1,610,424 control chromosomes in the GnomAD database, including 601,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52896 hom., cov: 32)
  • Exomes 𝑓: 0.87 (548914 hom.)
• Consequence: NLRP12 ENST00000492915.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.773
• Publications: 16 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-53807707-G-C is Benign according to our data. Variant chr19-53807707-G-C is described in ClinVar as Benign. ClinVar VariationId is 1230124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000492915.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	NM_144687.4	MANE Select	c.2073-42C>G		intron	N/A	NP_653288.1
	NLRP12	NM_001277126.2		c.2073-39C>G		intron	N/A	NP_001264055.1
	NLRP12	NM_001277129.1		c.2073-42C>G		intron	N/A	NP_001264058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000492915.1	TSL:1	n.999C>G		non_coding_transcript_exon	Exon 1 of 7
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.2073-42C>G		intron	N/A	ENSP00000319377.6
	NLRP12	ENST00000391773.8	TSL:1	c.2073-39C>G		intron	N/A	ENSP00000375653.1

Frequencies

GnomAD3 genomes AF: 0.831 AC: 126374 AN: 152012 Hom.: 52868 Cov.: 32

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.892

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.837

GnomAD2 exomes AF: 0.844 AC: 211813 AN: 250824 AF XY: 0.846

Gnomad AFR exome AF: 0.736

Gnomad AMR exome AF: 0.836

Gnomad ASJ exome AF: 0.852

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.882

Gnomad OTH exome AF: 0.855

GnomAD4 exome AF: 0.866 AC: 1263240 AN: 1458292 Hom.: 548914 Cov.: 30 AF XY: 0.864 AC XY: 627316 AN XY: 725656

African (AFR) AF: 0.727 AC: 24279 AN: 33404

American (AMR) AF: 0.838 AC: 37474 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 22285 AN: 26110

East Asian (EAS) AF: 0.691 AC: 27401 AN: 39674

South Asian (SAS) AF: 0.798 AC: 68710 AN: 86154

European-Finnish (FIN) AF: 0.886 AC: 47135 AN: 53182

Middle Eastern (MID) AF: 0.814 AC: 4691 AN: 5760

European-Non Finnish (NFE) AF: 0.883 AC: 979716 AN: 1109050

Other (OTH) AF: 0.855 AC: 51549 AN: 60260

GnomAD4 genome AF: 0.831 AC: 126457 AN: 152132 Hom.: 52896 Cov.: 32 AF XY: 0.832 AC XY: 61899 AN XY: 74376

African (AFR) AF: 0.737 AC: 30570 AN: 41492

American (AMR) AF: 0.857 AC: 13072 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2967 AN: 3472

East Asian (EAS) AF: 0.750 AC: 3870 AN: 5160

South Asian (SAS) AF: 0.802 AC: 3868 AN: 4824

European-Finnish (FIN) AF: 0.892 AC: 9458 AN: 10604

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.881 AC: 59901 AN: 68006

Other (OTH) AF: 0.835 AC: 1763 AN: 2112

Alfa AF: 0.839 Hom.: 5548

Bravo AF: 0.824

Asia WGS AF: 0.783 AC: 2721 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.066
DANN	Benign	0.85
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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: rs2866112; hg19: chr19-54310961; COSMIC: COSV60744911;