Genetic Variant NLRC4:p.Val1022Leu (chr2-32224484-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001199138.2(NLRC4):c.3064G>C(p.Val1022Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NLRC4
NM_001199138.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Publications

0 publications found

Variant links:

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 links:

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]

SLC30A6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16919166).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRC4	NM_001199138.2	MANE Select	c.3064G>C	p.Val1022Leu	missense	Exon 9 of 9	NP_001186067.1	Q9NPP4-1
NLRC4	NM_001199139.1		c.3064G>C	p.Val1022Leu	missense	Exon 9 of 9	NP_001186068.1	Q9NPP4-1
NLRC4	NM_021209.4		c.3064G>C	p.Val1022Leu	missense	Exon 9 of 9	NP_067032.3	Q9NPP4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.3064G>C	p.Val1022Leu	missense	Exon 9 of 9	ENSP00000385428.1	Q9NPP4-1
NLRC4	ENST00000360906.9	TSL:1	c.3064G>C	p.Val1022Leu	missense	Exon 9 of 9	ENSP00000354159.5	Q9NPP4-1
NLRC4	ENST00000342905.10	TSL:1	c.1069G>C	p.Val357Leu	missense	Exon 8 of 8	ENSP00000339666.6	Q9NPP4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

0.24

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.56

M_CAP

Benign

0.0093

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.97

PhyloP100

1.5

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.64

REVEL

Benign

0.043

Sift

Uncertain

0.019

Polyphen

0.0030

Vest4

0.25

MutPred

0.14

Loss of methylation at K1020 (P = 0.0843)

MVP

0.53

MPC

0.20

ClinPred

0.33

GERP RS

2.6

Varity_R

0.10

gMVP

0.10

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over