chr2-32251321-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001199138.2(NLRC4):c.543A>C(p.Arg181Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,613,658 control chromosomes in the GnomAD database, including 282,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 25910 hom., cov: 31)

Exomes 𝑓: 0.59 ( 256413 hom. )

Consequence

NLRC4
NM_001199138.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.266

Publications

20 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 Gene-Disease associations (from GenCC):

periodic fever-infantile enterocolitis-autoinflammatory syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina, Labcorp Genetics (formerly Invitae)
familial cold autoinflammatory syndrome 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

NLRC4 links:

ENSG00000289727 (HGNC:):

ENSG00000289727 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 2-32251321-T-G is Benign according to our data. Variant chr2-32251321-T-G is described in ClinVar as Benign. ClinVar VariationId is 403237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.266 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRC4	NM_001199138.2 link	c.543A>C	p.Arg181Arg	synonymous_variant	Exon 4 of 9	ENST00000402280.6	NP_001186067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6 link	c.543A>C	p.Arg181Arg	synonymous_variant	Exon 4 of 9	1	NM_001199138.2	ENSP00000385428.1

Frequencies

GnomAD3 genomes

AF:

0.581

AC:

88174

AN:

151794

Hom.:

25891

Cov.:

show subpopulations

Gnomad AFR

AF:

0.580

Gnomad AMI

AF:

0.613

Gnomad AMR

AF:

0.588

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.364

Gnomad SAS

AF:

0.449

Gnomad FIN

AF:

0.629

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.601

Gnomad OTH

AF:

0.591

GnomAD2 exomes

AF:

0.555

AC:

139463

AN:

251226

AF XY:

0.551

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.574

Gnomad ASJ exome

AF:

0.514

Gnomad EAS exome

AF:

0.345

Gnomad FIN exome

AF:

0.629

Gnomad NFE exome

AF:

0.595

Gnomad OTH exome

AF:

0.570

GnomAD4 exome

AF:

0.589

AC:

861105

AN:

1461748

Hom.:

256413

Cov.:

AF XY:

0.584

AC XY:

424630

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.582

AC:

19482

AN:

33472

American (AMR)

AF:

0.581

AC:

25979

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.516

AC:

13486

AN:

26136

East Asian (EAS)

AF:

0.388

AC:

15413

AN:

39682

South Asian (SAS)

AF:

0.467

AC:

40289

AN:

86254

European-Finnish (FIN)

AF:

0.629

AC:

33597

AN:

53406

Middle Eastern (MID)

AF:

0.514

AC:

2967

AN:

5768

European-Non Finnish (NFE)

AF:

0.607

AC:

674843

AN:

1111916

Other (OTH)

AF:

0.580

AC:

35049

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

21059

42118

63177

84236

105295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18200

36400

54600

72800

91000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.581

AC:

88233

AN:

151910

Hom.:

25910

Cov.:

AF XY:

0.581

AC XY:

43116

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.580

AC:

24047

AN:

41440

American (AMR)

AF:

0.588

AC:

8963

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

1733

AN:

3470

East Asian (EAS)

AF:

0.364

AC:

1866

AN:

5124

South Asian (SAS)

AF:

0.450

AC:

2165

AN:

4810

European-Finnish (FIN)

AF:

0.629

AC:

6651

AN:

10566

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.601

AC:

40864

AN:

67938

Other (OTH)

AF:

0.587

AC:

1234

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1901

3801

5702

7602

9503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

746

1492

2238

2984

3730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.593

Hom.:

11758

Bravo

AF:

0.577

Asia WGS

AF:

0.378

AC:

1318

AN:

3478

EpiCase

AF:

0.586

EpiControl

AF:

0.581

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 81% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Periodic fever-infantile enterocolitis-autoinflammatory syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cold autoinflammatory syndrome 4

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.0

(source)

DANN

Benign

0.64

PhyloP100

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over