2-32224609-T-A

Position:

• chr2-32224609-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001199138.2(NLRC4):​c.2939A>T​(p.Asp980Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D980H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.617

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRC4	NM_001199138.2	c.2939A>T	p.Asp980Val	missense_variant	9/9	ENST00000402280.6
NLRC4	NM_001199139.1	c.2939A>T	p.Asp980Val	missense_variant	9/9
NLRC4	NM_021209.4	c.2939A>T	p.Asp980Val	missense_variant	9/9
NLRC4	NM_001302504.1	c.944A>T	p.Asp315Val	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRC4	ENST00000402280.6	c.2939A>T	p.Asp980Val	missense_variant	9/9	1	NM_001199138.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 980 of the NLRC4 protein (p.Asp980Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NLRC4-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NLRC4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D;D;.;D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.77	.;.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;M;.;M
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.013	D;D;D;D
Polyphen		0.82	P;P;P;P
Vest4		0.59
MutPred		0.51		Loss of ubiquitination at K975 (P = 0.0661);Loss of ubiquitination at K975 (P = 0.0661);.;Loss of ubiquitination at K975 (P = 0.0661);
MVP		0.51
MPC		0.46
ClinPred		0.83	D
GERP RS		3.4
Varity_R		0.14
gMVP		0.39

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-32449678;