2-32235515-A-G

Position:

chr2-32235515-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.00040 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 27 hom. )

Consequence

NLRC4
NM_001199138.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.15

Variant links:

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

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. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NLRC4	NM_001199138.2 linkuse as main transcript	c.2668T>C	p.Cys890Arg	missense_variant	8/9	ENST00000402280.6	NP_001186067.1
NLRC4	NM_001199139.1 linkuse as main transcript	c.2668T>C	p.Cys890Arg	missense_variant	8/9		NP_001186068.1
NLRC4	NM_021209.4 linkuse as main transcript	c.2668T>C	p.Cys890Arg	missense_variant	8/9		NP_067032.3
NLRC4	NM_001302504.1 linkuse as main transcript	c.673T>C	p.Cys225Arg	missense_variant	7/8		NP_001289433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRC4	ENST00000402280.6 linkuse as main transcript	c.2668T>C	p.Cys890Arg	missense_variant	8/9	1	NM_001199138.2	ENSP00000385428	P1	Q9NPP4-1
	ENST00000697331.1 linkuse as main transcript	n.2130A>G		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00288

AC XY:

391

AN XY:

135792

show subpopulations

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.:

Cov.:

AF XY:

0.00146

AC XY:

1059

AN XY:

727234

show subpopulations

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:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74522

show subpopulations

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.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00248

AC:

301

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.58

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

LIST_S2

Benign

0.20

.;.;T;T

MetaRNN

Benign

0.0041

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;.;N

PrimateAI

Benign

0.31

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over