rs554602951

Positions:

chr19-53807532-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_144687.4(NLRP12):c.2206G>A(p.Gly736Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000324 in 1,614,140 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 10 hom. )

Consequence

NLRP12
NM_144687.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.59

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031626523).

BP6

Variant 19-53807532-C-T is Benign according to our data. Variant chr19-53807532-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536936.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000131 (20/152300) while in subpopulation SAS AF= 0.00414 (20/4828). AF 95% confidence interval is 0.00274. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP12	NM_144687.4 linkuse as main transcript	c.2206G>A	p.Gly736Arg	missense_variant	4/10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11 linkuse as main transcript	c.2206G>A	p.Gly736Arg	missense_variant	4/10	1	NM_144687.4	ENSP00000319377	P4	P59046-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152182

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:

0.00435

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000721

AC:

181

AN:

250908

Hom.:

AF XY:

0.000840

AC XY:

114

AN XY:

135690

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 SAS exome

AF:

0.00572

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000344

AC:

503

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

340

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00539

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000131

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000741

AC:

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 2

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 23, 2021	NLRP12 NM_144687 exon 4 p.Gly736Arg (c.2206G>A): This variant has not been reported in the literature but is present in 0.5% (176/30774) of South Asian alleles, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs554602951). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.18

T;.;.;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.0033

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.74

T;D;T;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.032

T;T;T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.2

M;M;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.6

D;D;D;D;N

REVEL

Pathogenic

0.68

Sift

Benign

0.18

T;T;T;T;T

Sift4G

Benign

0.067

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.70

MutPred

0.78

Gain of MoRF binding (P = 0.0286);Gain of MoRF binding (P = 0.0286);.;.;.;

MVP

0.94

MPC

0.36

ClinPred

0.21

GERP RS

2.8

Varity_R

0.17

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over