Genetic Variant NLRP12:p.Arg1016* (chr19-53795911-G-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_144687.4(NLRP12):c.3046C>T(p.Arg1016*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000975 in 1,614,096 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 8 hom. )

Consequence

NLRP12
NM_144687.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: -0.991

Publications

10 publications found

Variant links:

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

NLRP12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 19-53795911-G-A is Benign according to our data. Variant chr19-53795911-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 330001.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00426 (649/152226) while in subpopulation AFR AF = 0.0149 (618/41534). AF 95% confidence interval is 0.0139. There are 3 homozygotes in GnomAd4. There are 301 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 649 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRP12	NM_144687.4	MANE Select	c.3046C>T	p.Arg1016*	stop_gained	Exon 9 of 10	NP_653288.1	P59046-1
NLRP12	NM_001277126.2		c.3049C>T	p.Arg1017*	stop_gained	Exon 9 of 10	NP_001264055.1	P59046-7
NLRP12	NM_001277129.1		c.2875C>T	p.Arg959*	stop_gained	Exon 8 of 9	NP_001264058.1	P59046-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.3046C>T	p.Arg1016*	stop_gained	Exon 9 of 10	ENSP00000319377.6	P59046-1
NLRP12	ENST00000391773.8	TSL:1	c.3049C>T	p.Arg1017*	stop_gained	Exon 9 of 10	ENSP00000375653.1	P59046-7
NLRP12	ENST00000345770.9	TSL:1	c.2934-1775C>T		intron	N/A	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes

AF:

0.00427

AC:

650

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000853

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00128

AC:

321

AN:

251376

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.0167

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000325

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000632

AC:

924

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000583

AC XY:

424

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0168

AC:

561

AN:

33478

American (AMR)

AF:

0.000291

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000254

AC:

282

AN:

1112002

Other (OTH)

AF:

0.000944

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00426

AC:

649

AN:

152226

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

301

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0149

AC:

618

AN:

41534

American (AMR)

AF:

0.000852

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68028

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00181

Hom.:

Bravo

AF:

0.00498

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00166

AC:

202

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cold autoinflammatory syndrome 2 (4)

Autoinflammatory syndrome (1)

NLRP12-related disorder (1)

not provided (1)

Multisystem inflammatory syndrome in children (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Benign

0.95

Eigen

Benign

-0.086

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.021

PhyloP100

-0.99

Vest4

0.89

GERP RS

-1.3

Mutation Taster

=175/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over