Genetic Variant NLRC4:p.Gln514Gln (chr2-32250322-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001199138.2(NLRC4):c.1542A>G(p.Gln514Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,614,216 control chromosomes in the GnomAD database, including 259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 125 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 134 hom. )

Consequence

NLRC4
NM_001199138.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0110

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:

ENSG00000289727 (HGNC:):

ENSG00000289727 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 2-32250322-T-C is Benign according to our data. Variant chr2-32250322-T-C is described in ClinVar as [Benign]. Clinvar id is 475251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32250322-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.011 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRC4	NM_001199138.2 link	c.1542A>G	p.Gln514Gln	synonymous_variant	Exon 4 of 9	ENST00000402280.6	NP_001186067.1	Q9NPP4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6 link	c.1542A>G	p.Gln514Gln	synonymous_variant	Exon 4 of 9	1	NM_001199138.2	ENSP00000385428.1		Q9NPP4-1

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

3647

AN:

152214

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0822

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00896

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.00652

AC:

1637

AN:

251176

Hom.:

AF XY:

0.00466

AC XY:

633

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.0832

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000590

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00273

AC:

3984

AN:

1461884

Hom.:

134

Cov.:

AF XY:

0.00236

AC XY:

1719

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0829

Gnomad4 AMR exome

AF:

0.00425

Gnomad4 ASJ exome

AF:

0.00517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000418

Gnomad4 OTH exome

AF:

0.00629

GnomAD4 genome

AF:

0.0239

AC:

3647

AN:

152332

Hom.:

125

Cov.:

AF XY:

0.0225

AC XY:

1677

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0820

Gnomad4 AMR

AF:

0.00895

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.00762

Hom.:

Bravo

AF:

0.0277

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autoinflammatory syndrome

Benign:1

Apr 14, 2022

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

-0.98

CADD

Benign

0.34

DANN

Benign

0.20

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over