chr19-53809587-A-C

Variant names:

• chr19-53809587-A-C
• rs760012636
• NM_144687.4:c.2072T>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.2072T>G​(p.Leu691Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,458 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L691P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NLRP12 NM_144687.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001325
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.96
• Publications: 1 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=0.09587601).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144687.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	NM_144687.4	MANE Select	c.2072T>G	p.Leu691Arg	missense splice_region	Exon 3 of 10	NP_653288.1
	NLRP12	NM_001277126.2		c.2072T>G	p.Leu691Arg	missense splice_region	Exon 3 of 10	NP_001264055.1
	NLRP12	NM_001277129.1		c.2072T>G	p.Leu691Arg	missense splice_region	Exon 3 of 9	NP_001264058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.2072T>G	p.Leu691Arg	missense splice_region	Exon 3 of 10	ENSP00000319377.6
	NLRP12	ENST00000391773.8	TSL:1	c.2072T>G	p.Leu691Arg	missense splice_region	Exon 3 of 10	ENSP00000375653.1
	NLRP12	ENST00000345770.9	TSL:1	c.2072T>G	p.Leu691Arg	missense splice_region	Exon 3 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248138 AF XY: 0.00000742

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: 6.85e-7 AC: 1 AN: 1459458 Hom.: 0 Cov.: 40 AF XY: 0.00000138 AC XY: 1 AN XY: 725964

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5000

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111554

Other (OTH) AF: 0.00 AC: 0 AN: 60258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.41
DANN	Benign	0.59
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.90	T
PhyloP100		-3.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.13
Sift	Benign	0.14	T
Sift4G	Benign	0.49	T
Polyphen		0.0040	B
Vest4		0.10
MutPred		0.65		Gain of loop (P = 0.0166)
MVP		0.39
MPC		0.073
ClinPred		0.047	T
GERP RS		-2.3
Varity_R		0.069
gMVP		0.30
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.040
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: rs760012636; hg19: chr19-54312841;