rs606231460

Variant names:

• chr2-32250536-T-G
• rs606231460
• NM_001199138.2:c.1328A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001199138.2(NLRC4):​c.1328A>C​(p.His443Pro) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H443Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.77
• Publications: 33 publications found

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]

NLRC4 Gene-Disease associations (from GenCC):

• periodic fever-infantile enterocolitis-autoinflammatory syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina, Labcorp Genetics (formerly Invitae)
• familial cold autoinflammatory syndrome 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000289727 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-32250535-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 808727.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 2-32250536-T-G is Pathogenic according to our data. Variant chr2-32250536-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 161413.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199138.2. 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
	NLRC4	NM_001199138.2	MANE Select	c.1328A>C	p.His443Pro	missense	Exon 4 of 9	NP_001186067.1
	NLRC4	NM_001199139.1		c.1328A>C	p.His443Pro	missense	Exon 4 of 9	NP_001186068.1
	NLRC4	NM_021209.4		c.1328A>C	p.His443Pro	missense	Exon 4 of 9	NP_067032.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.1328A>C	p.His443Pro	missense	Exon 4 of 9	ENSP00000385428.1
	NLRC4	ENST00000360906.9	TSL:1	c.1328A>C	p.His443Pro	missense	Exon 4 of 9	ENSP00000354159.5
	NLRC4	ENST00000342905.10	TSL:1	c.262+1883A>C		intron	N/A	ENSP00000339666.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial cold autoinflammatory syndrome 4 (1)
1	-	-	Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.73
Sift	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.69		Gain of helix (P = 0.0082)
MVP		0.66
MPC		0.36
ClinPred		0.95	D
GERP RS		3.0
Varity_R		0.83
gMVP		0.65

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: rs606231460; hg19: chr2-32475605;