rs104895565

Variant names:

• chr19-53809584-T-TA
• rs104895565
• NM_144687.4:c.2072+2dupT

Your query was ambiguous. Multiple possible variants found:

• chr19-53809584-T-TA
• chr19-53809584-T-TAA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_144687.4(NLRP12):​c.2072+2dupT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,604,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: NLRP12 NM_144687.4 splice_donor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:1 O:1
• Conservation: PhyloP100: 1.31
• Publications: 6 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.2, offset of 37, new splice context is: tagGTtcgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000402 (60/149332) while in subpopulation AFR AF = 0.00125 (51/40826). AF 95% confidence interval is 0.000976. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 60 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.2072+2dupT		splice_donor intron	N/A	NP_653288.1	P59046-1
	NLRP12	NM_001277126.2		c.2072+2dupT		splice_donor intron	N/A	NP_001264055.1	P59046-7
	NLRP12	NM_001277129.1		c.2072+2dupT		splice_donor intron	N/A	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.2072+2_2072+3insT		splice_donor intron	N/A	ENSP00000319377.6	P59046-1
	NLRP12	ENST00000391773.8	TSL:1	c.2072+2_2072+3insT		splice_donor intron	N/A	ENSP00000375653.1	P59046-7
	NLRP12	ENST00000345770.9	TSL:1	c.2072+2_2072+3insT		splice_donor intron	N/A	ENSP00000341428.5	A0A0C4DH17

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 53 AN: 149280 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000671

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00119

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000109 AC: 27 AN: 247892 AF XY: 0.0000891

Gnomad AFR exome AF: 0.000958

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000493

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000715 AC: 104 AN: 1455266 Hom.: 0 Cov.: 40 AF XY: 0.0000705 AC XY: 51 AN XY: 723896

African (AFR) AF: 0.000871 AC: 29 AN: 33306

American (AMR) AF: 0.0000673 AC: 3 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.000760 AC: 30 AN: 39468

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52268

Middle Eastern (MID) AF: 0.000203 AC: 1 AN: 4926

European-Non Finnish (NFE) AF: 0.0000316 AC: 35 AN: 1108552

Other (OTH) AF: 0.0000833 AC: 5 AN: 60034

GnomAD4 genome AF: 0.000402 AC: 60 AN: 149332 Hom.: 0 Cov.: 32 AF XY: 0.000441 AC XY: 32 AN XY: 72556

African (AFR) AF: 0.00125 AC: 51 AN: 40826

American (AMR) AF: 0.0000670 AC: 1 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00119 AC: 6 AN: 5030

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67538

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.63		Position offset: -33
DS_DL_spliceai		0.57		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104895565; hg19: chr19-54312838; COSMIC: COSV60744297; COSMIC: COSV60744297;