Menu
GeneBe

rs148696946

chr2-32252591-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PVS1_StrongBP6_ModerateBS1BS2

The NM_001199138.2(NLRC4):c.90G>A(p.Trp30Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NLRC4
NM_001199138.2 stop_gained

Scores

2
2
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.688
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-32252591-C-T is Benign according to our data. Variant chr2-32252591-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 542043.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000164 (25/152330) while in subpopulation AFR AF= 0.000577 (24/41564). AF 95% confidence interval is 0.000398. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NLRC4NM_001199138.2 linkuse as main transcriptc.90G>A p.Trp30Ter stop_gained 3/9 ENST00000402280.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NLRC4ENST00000402280.6 linkuse as main transcriptc.90G>A p.Trp30Ter stop_gained 3/91 NM_001199138.2 P1Q9NPP4-1
ENST00000697331.1 linkuse as main transcriptn.2994-744C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000164
AC:
25
AN:
152212
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000437
AC:
11
AN:
251468
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.000554
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461818
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000164
AC:
25
AN:
152330
Hom.:
0
Cov.:
31
AF XY:
0.000215
AC XY:
16
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.000577
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000581
Hom.:
0
Bravo
AF:
0.000147
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000494
AC:
6
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeOct 09, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.39
Cadd
Pathogenic
28
Dann
Uncertain
0.98
Eigen
Uncertain
0.41
Eigen_PC
Benign
0.11
FATHMM_MKL
Benign
0.043
N
Vest4
0.89
GERP RS
2.3

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148696946; hg19: chr2-32477660; API