rs61754192

Variant names:

• chr2-32224763-C-A
• rs61754192
• NM_001199138.2:c.2785G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199138.2(NLRC4):​c.2785G>T​(p.Ala929Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,550,250 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (99 hom.)
• Consequence: NLRC4 NM_001199138.2 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.453
• Publications: 10 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049054623).
• BP6: Variant 2-32224763-C-A is Benign according to our data. Variant chr2-32224763-C-A is described in ClinVar as Benign. ClinVar VariationId is 475254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00769 (1162/151194) while in subpopulation NFE AF = 0.0115 (779/67892). AF 95% confidence interval is 0.0108. There are 4 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1162 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	NM_001199138.2	MANE Select	c.2785G>T	p.Ala929Ser	missense splice_region	Exon 9 of 9	NP_001186067.1
	NLRC4	NM_001199139.1		c.2785G>T	p.Ala929Ser	missense splice_region	Exon 9 of 9	NP_001186068.1
	NLRC4	NM_021209.4		c.2785G>T	p.Ala929Ser	missense splice_region	Exon 9 of 9	NP_067032.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.2785G>T	p.Ala929Ser	missense splice_region	Exon 9 of 9	ENSP00000385428.1
	NLRC4	ENST00000360906.9	TSL:1	c.2785G>T	p.Ala929Ser	missense splice_region	Exon 9 of 9	ENSP00000354159.5
	NLRC4	ENST00000342905.10	TSL:1	c.790G>T	p.Ala264Ser	missense splice_region	Exon 8 of 8	ENSP00000339666.6

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1162 AN: 151078 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00964

Gnomad ASJ AF: 0.00867

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000836

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00771

GnomAD2 exomes AF: 0.00754 AC: 1589 AN: 210810 AF XY: 0.00794

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00429

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.0000611

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0109 AC: 15244 AN: 1399056 Hom.: 99 Cov.: 26 AF XY: 0.0106 AC XY: 7326 AN XY: 693254

African (AFR) AF: 0.00145 AC: 45 AN: 30994

American (AMR) AF: 0.00501 AC: 167 AN: 33328

Ashkenazi Jewish (ASJ) AF: 0.00627 AC: 148 AN: 23592

East Asian (EAS) AF: 0.0000518 AC: 2 AN: 38608

South Asian (SAS) AF: 0.00168 AC: 128 AN: 76334

European-Finnish (FIN) AF: 0.00877 AC: 454 AN: 51790

Middle Eastern (MID) AF: 0.00275 AC: 15 AN: 5464

European-Non Finnish (NFE) AF: 0.0127 AC: 13718 AN: 1081390

Other (OTH) AF: 0.00985 AC: 567 AN: 57556

GnomAD4 genome AF: 0.00769 AC: 1162 AN: 151194 Hom.: 4 Cov.: 32 AF XY: 0.00762 AC XY: 562 AN XY: 73796

African (AFR) AF: 0.00180 AC: 74 AN: 41088

American (AMR) AF: 0.00963 AC: 146 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00867 AC: 30 AN: 3462

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.000837 AC: 4 AN: 4780

European-Finnish (FIN) AF: 0.0104 AC: 108 AN: 10354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0115 AC: 779 AN: 67892

Other (OTH) AF: 0.00763 AC: 16 AN: 2096

Alfa AF: 0.0104 Hom.: 21

Bravo AF: 0.00750

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0127 AC: 109

ExAC AF: 0.00676 AC: 820

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	NLRC4-related disorder (1)
-	-	1	not specified (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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.8
DANN	Benign	0.64
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.45
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.12
Sift	Benign	0.50	T
Polyphen		0.0020	B
Vest4		0.20
MVP		0.31
MPC		0.19
ClinPred		0.00065	T
GERP RS		-2.1
Varity_R		0.038
gMVP		0.078

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61754192; hg19: chr2-32449832; COSMIC: COSV50872296; COSMIC: COSV50872296;