chr19-53809646-G-C

Variant names:

• chr19-53809646-G-C
• rs781329641
• NM_144687.4:c.2013C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144687.4(NLRP12):​c.2013C>G​(p.Ser671Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S671S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0947451).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4	c.2013C>G	p.Ser671Arg	missense_variant	Exon 3 of 10	ENST00000324134.11	NP_653288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP12	ENST00000324134.11	c.2013C>G	p.Ser671Arg	missense_variant	Exon 3 of 10	1	NM_144687.4	ENSP00000319377.6
NLRP12	ENST00000345770.9	c.2013C>G	p.Ser671Arg	missense_variant	Exon 3 of 9	1		ENSP00000341428.5
NLRP12	ENST00000391772.1	c.2013C>G	p.Ser671Arg	missense_variant	Exon 3 of 7	1		ENSP00000375652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.049
DANN	Benign	0.83
DEOGEN2	Benign	0.076	T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.55	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.095	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.8	M;M;M;.;.
PhyloP100		-1.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.034	D;D;D;T;T
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.14	B;.;.;.;.
Vest4		0.17
MutPred		0.35		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.60
MPC		0.061
ClinPred		0.075	T
GERP RS		-6.6
Varity_R		0.099
gMVP		0.19
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs781329641; hg19: chr19-54312900;