rs61741169

Variant names:

• chr2-32249994-A-T
• rs61741169
• NM_001199138.2:c.1870T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-32249994-A-T
• chr2-32249994-A-G

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.1870T>A​(p.Trp624Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,614,144 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (23 hom.)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.56
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029858947).
• BP6: Variant 2-32249994-A-T is Benign according to our data. Variant chr2-32249994-A-T is described in ClinVar as Benign. ClinVar VariationId is 542044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00836 (1273/152256) while in subpopulation AFR AF = 0.0286 (1186/41540). AF 95% confidence interval is 0.0272. There are 23 homozygotes in GnomAd4. There are 610 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1273 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.1870T>A	p.Trp624Arg	missense	Exon 4 of 9	NP_001186067.1	Q9NPP4-1
	NLRC4	NM_001199139.1		c.1870T>A	p.Trp624Arg	missense	Exon 4 of 9	NP_001186068.1	Q9NPP4-1
	NLRC4	NM_021209.4		c.1870T>A	p.Trp624Arg	missense	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.1870T>A	p.Trp624Arg	missense	Exon 4 of 9	ENSP00000385428.1	Q9NPP4-1
	NLRC4	ENST00000360906.9	TSL:1	c.1870T>A	p.Trp624Arg	missense	Exon 4 of 9	ENSP00000354159.5	Q9NPP4-1
	NLRC4	ENST00000342905.10	TSL:1	c.262+2425T>A		intron	N/A	ENSP00000339666.6	Q9NPP4-2

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1265 AN: 152138 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00210 AC: 527 AN: 251412 AF XY: 0.00142

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000839 AC: 1226 AN: 1461888 Hom.: 23 Cov.: 32 AF XY: 0.000661 AC XY: 481 AN XY: 727244

African (AFR) AF: 0.0311 AC: 1042 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112012

Other (OTH) AF: 0.00189 AC: 114 AN: 60392

GnomAD4 genome AF: 0.00836 AC: 1273 AN: 152256 Hom.: 23 Cov.: 32 AF XY: 0.00819 AC XY: 610 AN XY: 74446

African (AFR) AF: 0.0286 AC: 1186 AN: 41540

American (AMR) AF: 0.00464 AC: 71 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.000672 Hom.: 5

Bravo AF: 0.00960

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not provided (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	0.075
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0070
DANN	Benign	0.32
DEOGEN2	Benign	0.081	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.6
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.044
Sift	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.066
MutPred		0.51		Gain of disorder (P = 0.0064)
MVP		0.13
MPC		0.36
ClinPred		0.0015	T
GERP RS		-6.5
Varity_R		0.041
gMVP		0.25

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: rs61741169; hg19: chr2-32475063;