rs1553347334

Positions:

• chr2-32250849-G-C
• chr2-32250849-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001199138.2(NLRC4):​c.1015C>G​(p.Leu339Val) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.38

Genes affected

NLRC4 (HGNC:16412): (NLR family CARD domain containing 4) This gene encodes a member of the caspase recruitment domain-containing NLR family. Family members play essential roles in innate immune response to a wide range of pathogenic organisms, tissue damage and other cellular stresses. Mutations in this gene result in autoinflammation with infantile enterocolitis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ENSG00000289727 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 2-32250849-G-C is Pathogenic according to our data. Variant chr2-32250849-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1694356.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRC4	NM_001199138.2	c.1015C>G	p.Leu339Val	missense_variant	4/9	ENST00000402280.6	NP_001186067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6	c.1015C>G	p.Leu339Val	missense_variant	4/9	1	NM_001199138.2	ENSP00000385428.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoinflammatory syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.76	.;.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.52
MutPred		0.80		Gain of MoRF binding (P = 0.1096);Gain of MoRF binding (P = 0.1096);Gain of MoRF binding (P = 0.1096);
MVP		0.71
MPC		0.77
ClinPred		0.95	D
GERP RS		2.4
Varity_R		0.20
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-32475918; COSMIC: COSV61595052;