Genetic Variant NLRP12:p.Tyr526Tyr (chr19-53810081-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2BP4_StrongBP6_ModerateBP7BS2

The NM_144687.4(NLRP12):c.1578T>C(p.Tyr526Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NLRP12
NM_144687.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.83

Publications

0 publications found

Variant links:

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

NLRP12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BP6

Variant 19-53810081-A-G is Benign according to our data. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-53810081-A-G is described in CliVar as Likely_benign. Clinvar id is 1932857.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.83 with no splicing effect.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP12	NM_144687.4 link	c.1578T>C	p.Tyr526Tyr	synonymous_variant	Exon 3 of 10	ENST00000324134.11	NP_653288.1	P59046-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NLRP12	ENST00000324134.11 link	c.1578T>C	p.Tyr526Tyr	synonymous_variant	Exon 3 of 10	1	NM_144687.4	ENSP00000319377.6	P59046-1
NLRP12	ENST00000345770.9 link	c.1578T>C	p.Tyr526Tyr	synonymous_variant	Exon 3 of 9	1		ENSP00000341428.5	A0A0C4DH17
NLRP12	ENST00000391772.1 link	c.1578T>C	p.Tyr526Tyr	synonymous_variant	Exon 3 of 7	1		ENSP00000375652.1	A0A0C4DFY3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 2

Benign:1

Jun 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.043

(source)

DANN

Benign

0.44

PhyloP100

-1.8

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over