19-55902194-C-T

Variant names:

• chr19-55902194-C-T
• rs1986202822
• NM_176810.2:c.2630G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_176810.2(NLRP13):​c.2630G>A​(p.Cys877Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NLRP13 NM_176810.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.475

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41070375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP13	NM_176810.2	c.2630G>A	p.Cys877Tyr	missense_variant	Exon 9 of 11	ENST00000342929.4	NP_789780.2
NLRP13	NM_001321057.1	c.2630G>A	p.Cys877Tyr	missense_variant	Exon 9 of 12		NP_001307986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP13	ENST00000342929.4	c.2630G>A	p.Cys877Tyr	missense_variant	Exon 9 of 11	1	NM_176810.2	ENSP00000343891.3
NLRP13	ENST00000588751.5	c.2630G>A	p.Cys877Tyr	missense_variant	Exon 9 of 12	5		ENSP00000467899.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461514 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2630G>A (p.C877Y) alteration is located in exon 9 (coding exon 9) of the NLRP13 gene. This alteration results from a G to A substitution at nucleotide position 2630, causing the cysteine (C) at amino acid position 877 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.29	.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.8	.;H
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-11	.;D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.33
MutPred		0.59		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.37
MPC		0.15
ClinPred		0.99	D
GERP RS		0.12
Varity_R		0.57
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs1986202822; hg19: chr19-56413560;