19-53798340-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_144687.4(NLRP12):​c.2830C>A​(p.Arg944Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,614,144 control chromosomes in the GnomAD database, including 28 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 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (25 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:1
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-53798340-G-T is Benign according to our data. Variant chr19-53798340-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97891.
• BP7: Synonymous conserved (PhyloP=0.335 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00324 (493/152274) while in subpopulation AMR AF = 0.00465 (71/15270). AF 95% confidence interval is 0.00396. There are 3 homozygotes in GnomAd4. There are 242 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 493 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>A	p.Arg944Arg	synonymous	Exon 8 of 10	NP_653288.1
	NLRP12	NM_001277126.2		c.2833C>A	p.Arg945Arg	synonymous	Exon 8 of 10	NP_001264055.1
	NLRP12	NM_001277129.1		c.2757-2311C>A		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>A	p.Arg944Arg	synonymous	Exon 8 of 10	ENSP00000319377.6
	NLRP12	ENST00000391773.8	TSL:1	c.2833C>A	p.Arg945Arg	synonymous	Exon 8 of 10	ENSP00000375653.1
	NLRP12	ENST00000345770.9	TSL:1	c.2833C>A	p.Arg945Arg	synonymous	Exon 8 of 9	ENSP00000341428.5

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 152156 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.00466

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00348 AC: 874 AN: 251242 AF XY: 0.00395

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00414 AC: 6046 AN: 1461870 Hom.: 25 Cov.: 32 AF XY: 0.00422 AC XY: 3068 AN XY: 727236

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00364 AC: 163 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

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

South Asian (SAS) AF: 0.00407 AC: 351 AN: 86258

European-Finnish (FIN) AF: 0.00195 AC: 104 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00464 AC: 5159 AN: 1111996

Other (OTH) AF: 0.00381 AC: 230 AN: 60394

GnomAD4 genome AF: 0.00324 AC: 493 AN: 152274 Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74452

African (AFR) AF: 0.000698 AC: 29 AN: 41572

American (AMR) AF: 0.00465 AC: 71 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00437 AC: 297 AN: 68026

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00345

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00557

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Familial cold autoinflammatory syndrome 2 (5)
-	-	2	not provided (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Familial cold autoinflammatory syndrome (1)
-	-	1	NLRP12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.1
DANN	Benign	0.45
PhyloP100		0.34
Mutation Taster		=100/0	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;