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:8 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: Illumina, Orphanet, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199138.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	NM_001199138.2	MANE Select	c.1824C>T	p.Ala608Ala	synonymous	Exon 4 of 9	NP_001186067.1	Q9NPP4-1
	NLRC4	NM_001199139.1		c.1824C>T	p.Ala608Ala	synonymous	Exon 4 of 9	NP_001186068.1	Q9NPP4-1
	NLRC4	NM_021209.4		c.1824C>T	p.Ala608Ala	synonymous	Exon 4 of 9	NP_067032.3	Q9NPP4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.1824C>T	p.Ala608Ala	synonymous	Exon 4 of 9	ENSP00000385428.1	Q9NPP4-1
	NLRC4	ENST00000360906.9	TSL:1	c.1824C>T	p.Ala608Ala	synonymous	Exon 4 of 9	ENSP00000354159.5	Q9NPP4-1
	NLRC4	ENST00000342905.10	TSL:1	c.262+2379C>T		intron	N/A	ENSP00000339666.6	Q9NPP4-2

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (3)
-	-	1	Familial cold autoinflammatory syndrome 4 (1)
-	-	1	Periodic fever-infantile enterocolitis-autoinflammatory syndrome (1)
-	-	1	Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

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;