2-32224544-G-A

Variant names:

• chr2-32224544-G-A
• rs372904047
• NM_001199138.2:c.3004C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001199138.2(NLRC4):​c.3004C>T​(p.Leu1002Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L1002I) 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: 0.329
• 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]

SLC30A6 (HGNC:19305): (solute carrier family 30 member 6) This gene encodes a member of a family of proteins that function as zinc transporters. This protein can regulate subcellular levels of zinc in the Golgi and vesicles. Expression of this gene is altered in the Alzheimer's disease brain plaques. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3004C>T	p.Leu1002Phe	missense	Exon 9 of 9	NP_001186067.1	Q9NPP4-1
	NLRC4	NM_001199139.1		c.3004C>T	p.Leu1002Phe	missense	Exon 9 of 9	NP_001186068.1	Q9NPP4-1
	NLRC4	NM_021209.4		c.3004C>T	p.Leu1002Phe	missense	Exon 9 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.3004C>T	p.Leu1002Phe	missense	Exon 9 of 9	ENSP00000385428.1	Q9NPP4-1
	NLRC4	ENST00000360906.9	TSL:1	c.3004C>T	p.Leu1002Phe	missense	Exon 9 of 9	ENSP00000354159.5	Q9NPP4-1
	NLRC4	ENST00000342905.10	TSL:1	c.1009C>T	p.Leu337Phe	missense	Exon 8 of 8	ENSP00000339666.6	Q9NPP4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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	Benign	0.30
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.33
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.24
Sift	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.54		Gain of sheet (P = 0.1208)
MVP		0.82
MPC		0.79
ClinPred		0.95	D
GERP RS		3.7
Varity_R		0.10
gMVP		0.23

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: rs372904047; hg19: chr2-32449613;