rs61741349

Variant names:

• chr19-53801228-G-A
• rs61741349
• NM_144687.4:c.2755C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-53801228-G-A
• chr19-53801228-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144687.4(NLRP12):​c.2755C>T​(p.Arg919Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,682 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R919Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0065 (17 hom., cov: 30)
  • Exomes 𝑓: 0.00074 (12 hom.)
• Consequence: NLRP12 NM_144687.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003798
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0430
• Publications: 6 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 (MetaRNN=0.013561815).
• BP6: Variant 19-53801228-G-A is Benign according to our data. Variant chr19-53801228-G-A is described in ClinVar as Benign. ClinVar VariationId is 330010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00649 (987/152032) while in subpopulation AFR AF = 0.0219 (908/41494). AF 95% confidence interval is 0.0207. There are 17 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 987 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	NM_144687.4	MANE Select	c.2755C>T	p.Arg919Trp	missense splice_region	Exon 7 of 10	NP_653288.1
	NLRP12	NM_001277126.2		c.2758C>T	p.Arg920Trp	missense splice_region	Exon 7 of 10	NP_001264055.1
	NLRP12	NM_001277129.1		c.2755C>T	p.Arg919Trp	missense splice_region	Exon 7 of 9	NP_001264058.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.2755C>T	p.Arg919Trp	missense splice_region	Exon 7 of 10	ENSP00000319377.6
	NLRP12	ENST00000391773.8	TSL:1	c.2758C>T	p.Arg920Trp	missense splice_region	Exon 7 of 10	ENSP00000375653.1
	NLRP12	ENST00000345770.9	TSL:1	c.2758C>T	p.Arg920Trp	missense splice_region	Exon 7 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 985 AN: 151914 Hom.: 18 Cov.: 30

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00303

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00172 AC: 430 AN: 250276 AF XY: 0.00117

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000738 AC: 1079 AN: 1461650 Hom.: 12 Cov.: 35 AF XY: 0.000634 AC XY: 461 AN XY: 727118

African (AFR) AF: 0.0233 AC: 779 AN: 33472

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.000169 AC: 188 AN: 1111824

Other (OTH) AF: 0.00103 AC: 62 AN: 60386

GnomAD4 genome AF: 0.00649 AC: 987 AN: 152032 Hom.: 17 Cov.: 30 AF XY: 0.00654 AC XY: 486 AN XY: 74296

African (AFR) AF: 0.0219 AC: 908 AN: 41494

American (AMR) AF: 0.00302 AC: 46 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67980

Other (OTH) AF: 0.00618 AC: 13 AN: 2104

Alfa AF: 0.00151 Hom.: 2

Bravo AF: 0.00713

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial cold autoinflammatory syndrome 2 (5)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.043
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.18
Sift	Benign	0.076	T
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.40
MVP		0.73
MPC		0.36
ClinPred		0.028	T
GERP RS		-0.83
Varity_R		0.12
gMVP		0.57
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.010		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: rs61741349; hg19: chr19-54304482;