rs34716166

Variant names:

• chr2-32235443-A-G
• rs34716166
• NM_001199138.2:c.2740T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.374
• Publications: 2 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=-0.76).
• 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.

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.2740T>C	p.Leu914Leu	synonymous	Exon 8 of 9	NP_001186067.1
	NLRC4	NM_001199139.1		c.2740T>C	p.Leu914Leu	synonymous	Exon 8 of 9	NP_001186068.1
	NLRC4	NM_021209.4		c.2740T>C	p.Leu914Leu	synonymous	Exon 8 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.2740T>C	p.Leu914Leu	synonymous	Exon 8 of 9	ENSP00000385428.1
	NLRC4	ENST00000360906.9	TSL:1	c.2740T>C	p.Leu914Leu	synonymous	Exon 8 of 9	ENSP00000354159.5
	NLRC4	ENST00000342905.10	TSL:1	c.745T>C	p.Leu249Leu	synonymous	Exon 7 of 8	ENSP00000339666.6

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152202 Hom.: 1 Cov.: 33

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

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.: 8 Cov.: 30 AF XY: 0.00168 AC XY: 1225 AN XY: 727208

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 470 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00325 AC: 280 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5768

European-Non Finnish (NFE) AF: 0.00112 AC: 1249 AN: 1111940

Other (OTH) AF: 0.00291 AC: 176 AN: 60394

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.00118 AC XY: 88 AN XY: 74490

African (AFR) AF: 0.000265 AC: 11 AN: 41572

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00236 Hom.: 1

Bravo AF: 0.00146

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	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	-0.76
CADD	Benign	6.3
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

Other links and lift over

dbSNP: rs34716166; hg19: chr2-32460512;