rs544969923

chr2-32235515-A-Gchr2-32235515-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199138.2(NLRC4):c.2668T>C(p.Cys890Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000956 in 1,614,226 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C890S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.15

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041139424).
• BP6: Variant 2-32235515-A-G is Benign according to our data. Variant chr2-32235515-A-G is described in ClinVar as [Benign]. Clinvar id is 542048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-32235515-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0004 (61/152368) while in subpopulation SAS AF= 0.012 (58/4828). AF 95% confidence interval is 0.00954. There are 2 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRC4	NM_001199138.2	c.2668T>C	p.Cys890Arg	missense_variant	8/9	ENST00000402280.6
NLRC4	NM_001199139.1	c.2668T>C	p.Cys890Arg	missense_variant	8/9
NLRC4	NM_021209.4	c.2668T>C	p.Cys890Arg	missense_variant	8/9
NLRC4	NM_001302504.1	c.673T>C	p.Cys225Arg	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRC4	ENST00000402280.6	c.2668T>C	p.Cys890Arg	missense_variant	8/9	1	NM_001199138.2	P1
	ENST00000697331.1	n.2130A>G		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152250 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00214 AC: 539 AN: 251300 Hom.: 12 AF XY: 0.00288 AC XY: 391 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00101 AC: 1483 AN: 1461858 Hom.: 27 Cov.: 31 AF XY: 0.00146 AC XY: 1059 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152368 Hom.: 2 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74522

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00248 AC: 301

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 03, 2022

- -

Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	1.0
Dann	Benign	0.54
DEOGEN2	Benign	0.11	T;T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0063	N
MetaRNN	Benign	0.0041	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.60	N;N;D;N
REVEL	Benign	0.044
Sift	Benign	0.14	T;T;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.29
MutPred		0.57		Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);.;Loss of loop (P = 0.0235);
MVP		0.30
MPC		0.37
ClinPred		0.035	T
GERP RS		-8.8
Varity_R		0.13
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs544969923; hg19: chr2-32460584;