chr19-53809587-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_144687.4(NLRP12):c.2072T>C(p.Leu691Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,609,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L691Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

NLRP12
NM_144687.4 missense, splice_region

Scores

Splicing: ADA: 0.00002931

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -2.96

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052826792).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000288 (42/1459458) while in subpopulation SAS AF = 0.000487 (42/86178). AF 95% confidence interval is 0.00037. There are 0 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. Median coverage is 40. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4 link	c.2072T>C	p.Leu691Pro	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000324134.11	NP_653288.1	P59046-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NLRP12	ENST00000324134.11 link	c.2072T>C	p.Leu691Pro	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_144687.4	ENSP00000319377.6	P59046-1
NLRP12	ENST00000345770.9 link	c.2072T>C	p.Leu691Pro	missense_variant, splice_region_variant	Exon 3 of 9	1		ENSP00000341428.5	A0A0C4DH17
NLRP12	ENST00000391772.1 link	c.2072T>C	p.Leu691Pro	missense_variant, splice_region_variant	Exon 3 of 7	1		ENSP00000375652.1	A0A0C4DFY3

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

149938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000645

AC:

AN:

248138

AF XY:

0.0000965

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1459458

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

725964

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000487

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5000

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111554

Other (OTH)

AF:

0.00

AC:

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000133

AC:

AN:

149938

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40956

American (AMR)

AF:

0.00

AC:

AN:

14888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.00

AC:

AN:

5080

South Asian (SAS)

AF:

0.000418

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67764

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.00

Hom.:

ExAC

AF:

0.0000989

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 2

Uncertain:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 691 of the NLRP12 protein (p.Leu691Pro). This variant is present in population databases (rs760012636, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NLRP12-related conditions. ClinVar contains an entry for this variant (Variation ID: 567056). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.87

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.28

T;.;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.35

T;T;T;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.053

T;T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

-3.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.66

N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.12

T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

0.0020

B;.;.;.;.

Vest4

0.078

MutPred

0.68

Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);

MVP

0.37

MPC

0.079

ClinPred

0.017

GERP RS

-2.3

Varity_R

0.061

gMVP

0.46

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000029

dbscSNV1_RF

Benign

0.020

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over