NM_144687.4:c.2830C>T

Variant names:

• chr19-53798340-G-A
• rs104895570
• NM_144687.4:c.2830C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_144687.4(NLRP12):​c.2830C>T​(p.Arg944Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,614,032 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R944Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: NLRP12 NM_144687.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.335
• Publications: 2 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23677921).
• BP6: Variant 19-53798340-G-A is Benign according to our data. Variant chr19-53798340-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 599430.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000213 (312/1461870) while in subpopulation NFE AF = 0.000253 (281/1111996). AF 95% confidence interval is 0.000228. There are 2 homozygotes in GnomAdExome4. There are 152 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 24 AD gene.

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.2830C>T	p.Arg944Trp	missense	Exon 8 of 10	NP_653288.1
	NLRP12	NM_001277126.2		c.2833C>T	p.Arg945Trp	missense	Exon 8 of 10	NP_001264055.1
	NLRP12	NM_001277129.1		c.2757-2311C>T		intron	N/A	NP_001264058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.2830C>T	p.Arg944Trp	missense	Exon 8 of 10	ENSP00000319377.6
	NLRP12	ENST00000391773.8	TSL:1	c.2833C>T	p.Arg945Trp	missense	Exon 8 of 10	ENSP00000375653.1
	NLRP12	ENST00000345770.9	TSL:1	c.2833C>T	p.Arg945Trp	missense	Exon 8 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000111 AC: 28 AN: 251242 AF XY: 0.0000957

Gnomad AFR exome AF: 0.000185

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: 0.000185

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000213 AC: 312 AN: 1461870 Hom.: 2 Cov.: 32 AF XY: 0.000209 AC XY: 152 AN XY: 727236

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000253 AC: 281 AN: 1111996

Other (OTH) AF: 0.000281 AC: 17 AN: 60394

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74326

African (AFR) AF: 0.000241 AC: 10 AN: 41450

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Autoinflammatory syndrome (1)
-	1	-	Familial cold autoinflammatory syndrome 2 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.030	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.34
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.10
Sift	Benign	0.15	T
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.28
MVP		0.85
MPC		0.23
ClinPred		0.14	T
GERP RS		0.83
Varity_R		0.066
gMVP		0.43
Mutation Taster		=88/12	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: rs104895570; hg19: chr19-54301594;