rs455060

Variant names:

• chr2-32250040-G-A
• rs455060
• NM_001199138.2:c.1824C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-32250040-G-A
• chr2-32250040-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001199138.2(NLRC4):​c.1824C>T​(p.Ala608Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,613,862 control chromosomes in the GnomAD database, including 302,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30064 hom., cov: 33)
  • Exomes 𝑓: 0.61 (272349 hom.)
• Consequence: NLRC4 NM_001199138.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.839
• Publications: 37 publications found

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)

ENSG00000289727 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-32250040-G-A is Benign according to our data. Variant chr2-32250040-G-A is described in ClinVar as Benign. ClinVar VariationId is 403236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.839 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRC4	NM_001199138.2	c.1824C>T	p.Ala608Ala	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	c.1824C>T	p.Ala608Ala	synonymous_variant	Exon 4 of 9	1	NM_001199138.2	ENSP00000385428.1

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95145 AN: 151992 Hom.: 30035 Cov.: 33

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.631

GnomAD2 exomes AF: 0.592 AC: 148955 AN: 251420 AF XY: 0.586

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.524

Gnomad EAS exome AF: 0.430

Gnomad FIN exome AF: 0.646

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.595

GnomAD4 exome AF: 0.608 AC: 889327 AN: 1461754 Hom.: 272349 Cov.: 58 AF XY: 0.604 AC XY: 439225 AN XY: 727176

African (AFR) AF: 0.687 AC: 23011 AN: 33476

American (AMR) AF: 0.657 AC: 29368 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 13717 AN: 26136

East Asian (EAS) AF: 0.480 AC: 19054 AN: 39692

South Asian (SAS) AF: 0.526 AC: 45412 AN: 86254

European-Finnish (FIN) AF: 0.646 AC: 34534 AN: 53418

Middle Eastern (MID) AF: 0.537 AC: 3096 AN: 5768

European-Non Finnish (NFE) AF: 0.616 AC: 684538 AN: 1111900

Other (OTH) AF: 0.606 AC: 36597 AN: 60386

GnomAD4 genome AF: 0.626 AC: 95225 AN: 152108 Hom.: 30064 Cov.: 33 AF XY: 0.627 AC XY: 46584 AN XY: 74352

African (AFR) AF: 0.681 AC: 28259 AN: 41478

American (AMR) AF: 0.649 AC: 9917 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1776 AN: 3468

East Asian (EAS) AF: 0.458 AC: 2367 AN: 5170

South Asian (SAS) AF: 0.520 AC: 2509 AN: 4828

European-Finnish (FIN) AF: 0.647 AC: 6842 AN: 10572

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41516 AN: 67994

Other (OTH) AF: 0.628 AC: 1326 AN: 2112

Alfa AF: 0.609 Hom.: 50221

Bravo AF: 0.628

Asia WGS AF: 0.482 AC: 1680 AN: 3478

EpiCase AF: 0.595

EpiControl AF: 0.591

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

not specified Benign:2

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 -

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 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -

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	-0.92
CADD	Benign	0.41
DANN	Benign	0.30
PhyloP100		-0.84

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

Other links and lift over

dbSNP: rs455060; hg19: chr2-32475109; COSMIC: COSV61591859;