16-50712018-C-T

Variant names:

• chr16-50712018-C-T
• rs5743277
• NM_001370466.1:c.2026C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001370466.1(NOD2):​c.2026C>T​(p.Arg676Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00395 in 1,613,156 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R676H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (16 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 4.39

Genes affected

NOD2 (HGNC:5331): (nucleotide binding oligomerization domain containing 2) This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068291724).
• BP6: Variant 16-50712018-C-T is Benign according to our data. Variant chr16-50712018-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197333.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6, Benign=1}. Variant chr16-50712018-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00331 (504/152384) while in subpopulation NFE AF = 0.00511 (348/68036). AF 95% confidence interval is 0.00467. There are 4 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2026C>T	p.Arg676Cys	missense_variant	Exon 4 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.2026C>T	p.Arg676Cys	missense_variant	Exon 4 of 12		NM_001370466.1	ENSP00000495993.1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 503 AN: 152266 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00321 AC: 798 AN: 248652 AF XY: 0.00317

Gnomad AFR exome AF: 0.000826

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00330

Gnomad EAS exome AF: 0.000764

Gnomad FIN exome AF: 0.00290

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00402 AC: 5866 AN: 1460772 Hom.: 16 Cov.: 33 AF XY: 0.00393 AC XY: 2856 AN XY: 726738

Gnomad4 AFR exome AF: 0.000627 AC: 21 AN: 33478

Gnomad4 AMR exome AF: 0.00136 AC: 61 AN: 44706

Gnomad4 ASJ exome AF: 0.00318 AC: 83 AN: 26110

Gnomad4 EAS exome AF: 0.000680 AC: 27 AN: 39700

Gnomad4 SAS exome AF: 0.000104 AC: 9 AN: 86240

Gnomad4 FIN exome AF: 0.00306 AC: 161 AN: 52564

Gnomad4 NFE exome AF: 0.00477 AC: 5305 AN: 1111850

Gnomad4 Remaining exome AF: 0.00323 AC: 195 AN: 60362

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152384 Hom.: 4 Cov.: 33 AF XY: 0.00299 AC XY: 223 AN XY: 74522

Gnomad4 AFR AF: 0.000793 AC: 0.000793269 AN: 0.000793269

Gnomad4 AMR AF: 0.00189 AC: 0.00189419 AN: 0.00189419

Gnomad4 ASJ AF: 0.00230 AC: 0.00230415 AN: 0.00230415

Gnomad4 EAS AF: 0.000578 AC: 0.000578258 AN: 0.000578258

Gnomad4 SAS AF: 0.000207 AC: 0.000206954 AN: 0.000206954

Gnomad4 FIN AF: 0.00188 AC: 0.00188253 AN: 0.00188253

Gnomad4 NFE AF: 0.00511 AC: 0.00511494 AN: 0.00511494

Gnomad4 OTH AF: 0.00284 AC: 0.00283554 AN: 0.00283554

Alfa AF: 0.00421 Hom.: 5

Bravo AF: 0.00350

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00327 AC: 397

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00439

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOD2: BP4, BS1, BS2 -

Jul 22, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with inflammatory bowel disease and other auto-inflammatory disorders (Lesage et al., 2002; Yao et al., 2012; Shen et al., 2015; Androletti et al., 2017; Burillo-Sanz et al., 2017; Li et al., 2020); Case control studies suggest this variant may be associated with Crohn's disease (Rivas et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in 0.32% (887/280050 alleles) in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32707200, 22942351, 26164256, 28814775, 28422189, 26070941, 11875755, 21983784, 33394828, 33927005, 35211104, 34975878) -

Oct 27, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome Uncertain:1

May 03, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Regional enteritis;C5201146:Blau syndrome Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inflammatory bowel disease 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Blau syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.3	.;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0030	.;D
Polyphen		1.0	D;D
Vest4		0.42
MVP		0.91
MPC		0.45
ClinPred		0.037	T
GERP RS		3.7
Varity_R		0.26
gMVP		0.52
Mutation Taster		=85/15	polymorphism

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

LitVar

Other links and lift over

dbSNP: rs5743277; hg19: chr16-50745929; COSMIC: COSV107363629; COSMIC: COSV107363629;