rs2066845

Variant names:

• chr16-50722629-G-C
• rs2066845
• NM_001370466.1:c.2641G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-50722629-G-C
• chr16-50722629-G-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.2641G>C​(p.Gly881Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0129 in 1,614,104 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G881C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 32)
  • Exomes 𝑓: 0.013 (236 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:5 B:5 O:3
• Conservation: PhyloP100: 4.50
• Publications: 741 publications found

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]

NOD2 Gene-Disease associations (from GenCC):

• Blau syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina
• inflammatory bowel disease 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.010364234).
• BP6: Variant 16-50722629-G-C is Benign according to our data. Variant chr16-50722629-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity|association. ClinVar VariationId is 4692.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1573/152288) while in subpopulation NFE AF = 0.0147 (997/68010). AF 95% confidence interval is 0.0139. There are 9 homozygotes in GnomAd4. There are 745 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1573 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370466.1. 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
	NOD2	NM_001370466.1	MANE Select	c.2641G>C	p.Gly881Arg	missense	Exon 8 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2722G>C	p.Gly908Arg	missense	Exon 8 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2641G>C	p.Gly881Arg	missense	Exon 7 of 11	NP_001280486.1	Q9HC29-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.2641G>C	p.Gly881Arg	missense	Exon 8 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2722G>C	p.Gly908Arg	missense	Exon 8 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000534057.1	TSL:1	c.355G>C	p.Gly119Arg	missense	Exon 4 of 5	ENSP00000437246.1	H0YF53

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1571 AN: 152170 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0113 AC: 2837 AN: 251458 AF XY: 0.0118

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00890

Gnomad ASJ exome AF: 0.0463

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00309

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0131 AC: 19221 AN: 1461816 Hom.: 236 Cov.: 31 AF XY: 0.0133 AC XY: 9644 AN XY: 727210

African (AFR) AF: 0.00227 AC: 76 AN: 33480

American (AMR) AF: 0.00854 AC: 382 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 1105 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00907 AC: 782 AN: 86256

European-Finnish (FIN) AF: 0.00292 AC: 156 AN: 53420

Middle Eastern (MID) AF: 0.0380 AC: 219 AN: 5768

European-Non Finnish (NFE) AF: 0.0141 AC: 15684 AN: 1111936

Other (OTH) AF: 0.0135 AC: 815 AN: 60396

GnomAD4 genome AF: 0.0103 AC: 1573 AN: 152288 Hom.: 9 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74466

African (AFR) AF: 0.00274 AC: 114 AN: 41556

American (AMR) AF: 0.0138 AC: 212 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4830

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 997 AN: 68010

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0127 Hom.: 24

Bravo AF: 0.0101

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.00992 AC: 1204

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; association

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Blau syndrome (2)
-	1	1	Inflammatory bowel disease 1 (3)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	1	-	not specified (1)
-	1	-	Psoriatic arthritis, susceptibility to;C4310620:Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 (1)
-	1	-	Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 (1)
-	-	-	Regional enteritis;C5201146:Blau syndrome (1)
-	-	-	Yao syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.98	L
PhyloP100		4.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.75
MPC		0.54
ClinPred		0.029	T
GERP RS		5.9
Varity_R		0.83
gMVP		0.56
Mutation Taster		=77/23	polymorphism (auto)

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: rs2066845; hg19: chr16-50756540; COSMIC: COSV56054563; COSMIC: COSV56054563;