2-32250110-T-G

Position:

• chr2-32250110-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001199138.2(NLRC4):​c.1754A>C​(p.Tyr585Ser) 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 benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y585C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22334221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRC4	NM_001199138.2	c.1754A>C	p.Tyr585Ser	missense_variant	4/9	ENST00000402280.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRC4	ENST00000402280.6	c.1754A>C	p.Tyr585Ser	missense_variant	4/9	1	NM_001199138.2	P1
	ENST00000697331.1	n.2994-3225T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 24, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with NLRC4-related conditions. This sequence change replaces tyrosine with serine at codon 585 of the NLRC4 protein (p.Tyr585Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.56	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.28	T;T;T
Polyphen		0.74	P;P;P
Vest4		0.41
MutPred		0.56		Gain of disorder (P = 0.0069);Gain of disorder (P = 0.0069);Gain of disorder (P = 0.0069);
MVP		0.61
MPC		0.67
ClinPred		0.21	T
GERP RS		1.9
Varity_R		0.19
gMVP		0.35

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: rs763410160; hg19: chr2-32475179;