19-53810222-C-T

Variant names:

• chr19-53810222-C-T
• rs77667763
• NM_144687.4:c.1437G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144687.4(NLRP12):​c.1437G>A​(p.Gln479Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,614,164 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: NLRP12 NM_144687.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.469
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-53810222-C-T is Benign according to our data. Variant chr19-53810222-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 536947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.469 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00286 (435/152278) while in subpopulation AFR AF = 0.00982 (408/41564). AF 95% confidence interval is 0.00903. There are 2 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 435 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	NM_144687.4	MANE Select	c.1437G>A	p.Gln479Gln	synonymous	Exon 3 of 10	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.1437G>A	p.Gln479Gln	synonymous	Exon 3 of 10	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.1437G>A	p.Gln479Gln	synonymous	Exon 3 of 9	NP_001264058.1	P59046-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP12	ENST00000324134.11	TSL:1 MANE Select	c.1437G>A	p.Gln479Gln	synonymous	Exon 3 of 10	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.1437G>A	p.Gln479Gln	synonymous	Exon 3 of 10	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.1437G>A	p.Gln479Gln	synonymous	Exon 3 of 9	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 425 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00963

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000807 AC: 203 AN: 251484 AF XY: 0.000567

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000344 AC: 503 AN: 1461886 Hom.: 1 Cov.: 40 AF XY: 0.000326 AC XY: 237 AN XY: 727244

African (AFR) AF: 0.0111 AC: 370 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.00129 AC: 78 AN: 60396

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152278 Hom.: 2 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74456

African (AFR) AF: 0.00982 AC: 408 AN: 41564

American (AMR) AF: 0.000719 AC: 11 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00340

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial cold autoinflammatory syndrome 2 (3)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.9
DANN	Benign	0.61
PhyloP100		-0.47
Mutation Taster		=89/11	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: rs77667763; hg19: chr19-54313476;