NM_176810.2:c.2822G>T

Variant names:

• chr19-55898905-C-A
• rs773555501
• NM_176810.2:c.2822G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_176810.2(NLRP13):​c.2822G>T​(p.Cys941Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C941Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP13 NM_176810.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• Publications: 1 publications found

Genes affected

NLRP13 (HGNC:22937): (NLR family pyrin domain containing 13) This gene encodes a member of the NACHT, leucine rich repeat, and PYD containing (NLRP) protein family. It has an N-terminal pyrin domain, followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. NLRP proteins are implicated in the activation of proinflammatory caspases through multiprotein complexes called inflammasomes. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP13	NM_176810.2	c.2822G>T	p.Cys941Phe	missense_variant	Exon 10 of 11	ENST00000342929.4	NP_789780.2
NLRP13	NM_001321057.1	c.2822G>T	p.Cys941Phe	missense_variant	Exon 10 of 12		NP_001307986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP13	ENST00000342929.4	c.2822G>T	p.Cys941Phe	missense_variant	Exon 10 of 11	1	NM_176810.2	ENSP00000343891.3
NLRP13	ENST00000588751.5	c.2822G>T	p.Cys941Phe	missense_variant	Exon 10 of 12	5		ENSP00000467899.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0063	T
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.1	.;M
PhyloP100		3.3
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-10	.;D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.24	.;B
Vest4		0.61
MutPred		0.85		Gain of catalytic residue at C941 (P = 0.089);Gain of catalytic residue at C941 (P = 0.089);
MVP		0.68
MPC		0.021
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.55
gMVP		0.64
Mutation Taster		=76/24	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: rs773555501; hg19: chr19-56410271;