2-32251321-T-G

Variant names:

• chr2-32251321-T-G
• rs408813
• NM_001199138.2:c.543A>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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.266
• Publications: 20 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=-0.54).
• 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.

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.543A>C	p.Arg181Arg	synonymous	Exon 4 of 9	NP_001186067.1
	NLRC4	NM_001199139.1		c.543A>C	p.Arg181Arg	synonymous	Exon 4 of 9	NP_001186068.1
	NLRC4	NM_021209.4		c.543A>C	p.Arg181Arg	synonymous	Exon 4 of 9	NP_067032.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.543A>C	p.Arg181Arg	synonymous	Exon 4 of 9	ENSP00000385428.1
	NLRC4	ENST00000360906.9	TSL:1	c.543A>C	p.Arg181Arg	synonymous	Exon 4 of 9	ENSP00000354159.5
	NLRC4	ENST00000342905.10	TSL:1	c.262+1098A>C		intron	N/A	ENSP00000339666.6

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88174 AN: 151794 Hom.: 25891 Cov.: 31

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

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.: 59 AF XY: 0.584 AC XY: 424630 AN XY: 727174

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

GnomAD4 genome AF: 0.581 AC: 88233 AN: 151910 Hom.: 25910 Cov.: 31 AF XY: 0.581 AC XY: 43116 AN XY: 74246

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

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Familial cold autoinflammatory syndrome 4 (1)
-	-	1	not provided (2)
-	-	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	-0.54
CADD	Benign	6.0
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

Other links and lift over

dbSNP: rs408813; hg19: chr2-32476390; COSMIC: COSV61591869;