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.1731G>A(p.Lys577Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,614,138 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

NLRP12
NM_144687.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.460

Publications

1 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=-0.78).

BP6

Variant 19-53809928-C-T is Benign according to our data. Variant chr19-53809928-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 536946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.46 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00126 (192/152296) while in subpopulation AFR AF = 0.00428 (178/41572). AF 95% confidence interval is 0.00377. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 192 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.1731G>A	p.Lys577Lys	synonymous	Exon 3 of 10	NP_653288.1
NLRP12	NM_001277126.2		c.1731G>A	p.Lys577Lys	synonymous	Exon 3 of 10	NP_001264055.1
NLRP12	NM_001277129.1		c.1731G>A	p.Lys577Lys	synonymous	Exon 3 of 9	NP_001264058.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.1731G>A	p.Lys577Lys	synonymous	Exon 3 of 10	ENSP00000319377.6
NLRP12	ENST00000391773.8	TSL:1	c.1731G>A	p.Lys577Lys	synonymous	Exon 3 of 10	ENSP00000375653.1
NLRP12	ENST00000345770.9	TSL:1	c.1731G>A	p.Lys577Lys	synonymous	Exon 3 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

187

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000346

AC:

AN:

251386

AF XY:

0.000236

show subpopulations

Gnomad AFR exome

AF:

0.00461

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000159

AC:

232

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

110

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00520

AC:

174

AN:

33480

American (AMR)

AF:

0.000313

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152296

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00428

AC:

178

AN:

41572

American (AMR)

AF:

0.000393

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000726

Hom.:

Bravo

AF:

0.00163

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cold autoinflammatory syndrome 2 (2)

Autoinflammatory syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.4

(source)

DANN

Benign

0.75

PhyloP100

-0.46

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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NM_144687.4:c.1731G>A

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