Variant rs750186083 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144687.4(NLRP12):c.619C>T(p.Pro207Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P207P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NLRP12
NM_144687.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.10

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21392548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP12	NM_144687.4 linkuse as main transcript	c.619C>T	p.Pro207Ser	missense_variant	3/10	ENST00000324134.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP12	ENST00000324134.11 linkuse as main transcript	c.619C>T	p.Pro207Ser	missense_variant	3/10	1	NM_144687.4	P4	P59046-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250792

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460554

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726288

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 02, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NLRP12-related disease. This variant is present in population databases (rs750186083, ExAC 0.002%). This sequence change replaces proline with serine at codon 207 of the NLRP12 protein (p.Pro207Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.45

DEOGEN2

Benign

0.038

T;.;.;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.53

T;T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.49

N;N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.79

N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.91

T;T;T;T;T

Sift4G

Benign

0.87

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.35

MutPred

0.30

Gain of phosphorylation at P207 (P = 0.0208);Gain of phosphorylation at P207 (P = 0.0208);Gain of phosphorylation at P207 (P = 0.0208);Gain of phosphorylation at P207 (P = 0.0208);Gain of phosphorylation at P207 (P = 0.0208);

MVP

0.86

MPC

0.35

ClinPred

0.16

GERP RS

4.3

Varity_R

0.061

gMVP

0.29

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

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