chr19-53805300-C-T

Variant names:

• chr19-53805300-C-T
• rs4806773
• NM_144687.4:c.2394G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144687.4(NLRP12):​c.2394G>A​(p.Gln798Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.866 in 1,613,798 control chromosomes in the GnomAD database, including 607,693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (54876 hom., cov: 30)
  • Exomes 𝑓: 0.87 (552817 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.62
• Publications: 25 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-53805300-C-T is Benign according to our data. Variant chr19-53805300-C-T is described in ClinVar as Benign. ClinVar VariationId is 403242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.62 with no splicing effect.
• 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: NM_144687.4. 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.2394G>A	p.Gln798Gln	synonymous	Exon 5 of 10	NP_653288.1
	NLRP12	NM_001277126.2		c.2397G>A	p.Gln799Gln	synonymous	Exon 5 of 10	NP_001264055.1
	NLRP12	NM_001277129.1		c.2394G>A	p.Gln798Gln	synonymous	Exon 5 of 9	NP_001264058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.2394G>A	p.Gln798Gln	synonymous	Exon 5 of 10	ENSP00000319377.6
	NLRP12	ENST00000391773.8	TSL:1	c.2397G>A	p.Gln799Gln	synonymous	Exon 5 of 10	ENSP00000375653.1
	NLRP12	ENST00000345770.9	TSL:1	c.2397G>A	p.Gln799Gln	synonymous	Exon 5 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes AF: 0.849 AC: 128952 AN: 151962 Hom.: 54843 Cov.: 30

Gnomad AFR AF: 0.796

Gnomad AMI AF: 0.829

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.800

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.855

GnomAD2 exomes AF: 0.849 AC: 213437 AN: 251340 AF XY: 0.849

Gnomad AFR exome AF: 0.796

Gnomad AMR exome AF: 0.839

Gnomad ASJ exome AF: 0.854

Gnomad EAS exome AF: 0.747

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.882

Gnomad OTH exome AF: 0.858

GnomAD4 exome AF: 0.868 AC: 1269291 AN: 1461718 Hom.: 552817 Cov.: 52 AF XY: 0.866 AC XY: 630022 AN XY: 727158

African (AFR) AF: 0.788 AC: 26389 AN: 33478

American (AMR) AF: 0.842 AC: 37658 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 22352 AN: 26134

East Asian (EAS) AF: 0.690 AC: 27397 AN: 39690

South Asian (SAS) AF: 0.797 AC: 68785 AN: 86254

European-Finnish (FIN) AF: 0.885 AC: 47276 AN: 53398

Middle Eastern (MID) AF: 0.818 AC: 4716 AN: 5764

European-Non Finnish (NFE) AF: 0.884 AC: 982814 AN: 1111894

Other (OTH) AF: 0.860 AC: 51904 AN: 60384

GnomAD4 genome AF: 0.849 AC: 129042 AN: 152080 Hom.: 54876 Cov.: 30 AF XY: 0.849 AC XY: 63086 AN XY: 74342

African (AFR) AF: 0.796 AC: 33011 AN: 41482

American (AMR) AF: 0.866 AC: 13194 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 2969 AN: 3470

East Asian (EAS) AF: 0.747 AC: 3841 AN: 5140

South Asian (SAS) AF: 0.800 AC: 3863 AN: 4826

European-Finnish (FIN) AF: 0.891 AC: 9441 AN: 10600

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.881 AC: 59929 AN: 68002

Other (OTH) AF: 0.852 AC: 1799 AN: 2112

Alfa AF: 0.867 Hom.: 237990

Bravo AF: 0.844

Asia WGS AF: 0.788 AC: 2739 AN: 3478

EpiCase AF: 0.873

EpiControl AF: 0.874

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial cold autoinflammatory syndrome 2 (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.032
DANN	Benign	0.42
PhyloP100		-1.6
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: rs4806773; hg19: chr19-54308554; COSMIC: COSV60744013;