chr2-32235443-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001199138.2(NLRC4):c.2740T>C(p.Leu914Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,614,130 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 8 hom. )

Consequence

NLRC4
NM_001199138.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.374

Publications

2 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=-0.76).

BP6

Variant 2-32235443-A-G is Benign according to our data. Variant chr2-32235443-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.374 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00126 (192/152320) while in subpopulation SAS AF = 0.00249 (12/4822). AF 95% confidence interval is 0.00144. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 192 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRC4	NM_001199138.2 link	c.2740T>C	p.Leu914Leu	synonymous_variant	Exon 8 of 9	ENST00000402280.6	NP_001186067.1	Q9NPP4-1
NLRC4	NM_001199139.1 link	c.2740T>C	p.Leu914Leu	synonymous_variant	Exon 8 of 9		NP_001186068.1	Q9NPP4-1
NLRC4	NM_021209.4 link	c.2740T>C	p.Leu914Leu	synonymous_variant	Exon 8 of 9		NP_067032.3	Q9NPP4-1
NLRC4	NM_001302504.1 link	c.745T>C	p.Leu249Leu	synonymous_variant	Exon 7 of 8		NP_001289433.1	Q9NPP4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6 link	c.2740T>C	p.Leu914Leu	synonymous_variant	Exon 8 of 9	1	NM_001199138.2	ENSP00000385428.1		Q9NPP4-1

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00202

AC:

507

AN:

251364

AF XY:

0.00217

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00157

AC:

2297

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1225

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00103

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0180

AC:

470

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00325

AC:

280

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00112

AC:

1249

AN:

1111940

Other (OTH)

AF:

0.00291

AC:

176

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

124

248

373

497

621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00126

AC:

192

AN:

152320

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41572

American (AMR)

AF:

0.000915

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00249

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00132

AC:

AN:

68030

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00236

Hom.:

Bravo

AF:

0.00146

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00224

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NLRC4: BP4, BP7 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely 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: Silent variant not near splice site -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Mar 04, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

-0.76

CADD

Benign

6.3

(source)

DANN

Benign

0.55

PhyloP100

-0.37

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over