NLRC4 p.Cys890Ser

Variant names:

• chr2-32235514-C-G
• NM_001199138.2:c.2669G>C
• NLRC4 p.Cys890Ser

Your query was ambiguous. Multiple possible variants found:

• chr2-32235514-C-G
• chr2-32235515-A-T
• chr2-32235513-AC-GG
• chr2-32235513-AC-TG
• chr2-32235513-AC-CG
• chr2-32235513-ACA-GCT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001199138.2(NLRC4):​c.2669G>C​(p.Cys890Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C890R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75
• Publications: 0 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: Illumina, Orphanet, 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041615635).

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.2669G>C	p.Cys890Ser	missense	Exon 8 of 9	NP_001186067.1	Q9NPP4-1
	NLRC4	NM_001199139.1		c.2669G>C	p.Cys890Ser	missense	Exon 8 of 9	NP_001186068.1	Q9NPP4-1
	NLRC4	NM_021209.4		c.2669G>C	p.Cys890Ser	missense	Exon 8 of 9	NP_067032.3	Q9NPP4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.2669G>C	p.Cys890Ser	missense	Exon 8 of 9	ENSP00000385428.1	Q9NPP4-1
	NLRC4	ENST00000360906.9	TSL:1	c.2669G>C	p.Cys890Ser	missense	Exon 8 of 9	ENSP00000354159.5	Q9NPP4-1
	NLRC4	ENST00000342905.10	TSL:1	c.674G>C	p.Cys225Ser	missense	Exon 7 of 8	ENSP00000339666.6	Q9NPP4-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.66
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-1.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.071
Sift	Benign	0.92	T
Varity_R		0.038
gMVP		0.19

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-32460583;