chr19-53807597-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_144687.4(NLRP12):c.2141A>G(p.Asn714Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,868 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N714K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 26 hom. )

Consequence

NLRP12
NM_144687.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.236

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01667121).

BP6

Variant 19-53807597-T-C is Benign according to our data. Variant chr19-53807597-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00264 (402/151998) while in subpopulation NFE AF = 0.00141 (96/67954). AF 95% confidence interval is 0.00118. There are 7 homozygotes in GnomAd4. There are 279 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4 link	c.2141A>G	p.Asn714Ser	missense_variant	Exon 4 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NLRP12	ENST00000324134.11 link	c.2141A>G	p.Asn714Ser	missense_variant	Exon 4 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9 link	c.2144A>G	p.Asn715Ser	missense_variant	Exon 4 of 9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1 link	c.2144A>G	p.Asn715Ser	missense_variant	Exon 4 of 7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

402

AN:

151880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00336

AC:

846

AN:

251468

AF XY:

0.00337

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00195

AC:

2852

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1361

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0247

AC:

1320

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00129

AC:

1440

AN:

1111998

Other (OTH)

AF:

0.00142

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

164

328

493

657

821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00264

AC:

402

AN:

151998

Hom.:

Cov.:

AF XY:

0.00376

AC XY:

279

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41468

American (AMR)

AF:

0.000131

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0282

AC:

298

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

67954

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

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:

0.00112

Hom.:

Bravo

AF:

0.000593

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00282

AC:

343

EpiCase

AF:

0.000654

EpiControl

AF:

0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NLRP12: BP4, BS1 -

Familial cold autoinflammatory syndrome 2

Benign:2

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Apr 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cold autoinflammatory syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.29

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.19

T;.;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.17

T;T;T;T;T

MetaRNN

Benign

0.017

T;T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.39

N;N;.;.;.

PhyloP100

-0.24

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.3

N;N;N;N;N

REVEL

Benign

0.090

Sift

Benign

0.27

T;T;T;T;T

Sift4G

Benign

0.36

T;T;T;T;T

Polyphen

0.090

B;.;.;.;.

Vest4

0.053

MVP

0.73

MPC

0.054

ClinPred

0.034

GERP RS

0.27

Varity_R

0.12

gMVP

0.084

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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