Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_144687.4(NLRP12):c.2784C>T(p.Ala928Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,614,090 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 34 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 33 hom. )

Consequence

NLRP12
NM_144687.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -3.60

Publications

2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine

NLRP12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-53798386-G-A is Benign according to our data. Variant chr19-53798386-G-A is described in ClinVar as Benign. ClinVar VariationId is 97890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.6 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1867/152258) while in subpopulation AFR AF = 0.0411 (1707/41552). AF 95% confidence interval is 0.0395. There are 34 homozygotes in GnomAd4. There are 881 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1867 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
NLRP12	NM_144687.4	MANE Select	c.2784C>T	p.Ala928Ala	synonymous	Exon 8 of 10	NP_653288.1
NLRP12	NM_001277126.2		c.2787C>T	p.Ala929Ala	synonymous	Exon 8 of 10	NP_001264055.1
NLRP12	NM_001277129.1		c.2757-2357C>T		intron	N/A	NP_001264058.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.2784C>T	p.Ala928Ala	synonymous	Exon 8 of 10	ENSP00000319377.6
NLRP12	ENST00000391773.8	TSL:1	c.2787C>T	p.Ala929Ala	synonymous	Exon 8 of 10	ENSP00000375653.1
NLRP12	ENST00000345770.9	TSL:1	c.2787C>T	p.Ala929Ala	synonymous	Exon 8 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1863

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00616

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00958

GnomAD2 exomes

AF:

0.00366

AC:

916

AN:

250598

AF XY:

0.00271

show subpopulations

Gnomad AFR exome

AF:

0.0463

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.000896

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000380

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00154

AC:

2249

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

974

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0454

AC:

1519

AN:

33480

American (AMR)

AF:

0.00351

AC:

157

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000918

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000139

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000295

AC:

328

AN:

1111996

Other (OTH)

AF:

0.00303

AC:

183

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

134

268

402

536

670

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.0123

AC:

1867

AN:

152258

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

881

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0411

AC:

1707

AN:

41552

American (AMR)

AF:

0.00609

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68028

Other (OTH)

AF:

0.00948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

181

271

362

452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00521

Hom.:

Bravo

AF:

0.0143

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cold autoinflammatory syndrome 2 (4)

Autoinflammatory syndrome (1)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.2

(source)

DANN

Benign

0.36

PhyloP100

-3.6

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over