chr16-50712283-G-A

Variant names:

• chr16-50712283-G-A
• rs104895464
• NM_001370466.1:c.2291G>A

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.2291G>A​(p.Arg764Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,998 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R764W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5 O:1
• Conservation: PhyloP100: -0.116
• Publications: 14 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: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• 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=0.0066200793).
• BP6: Variant 16-50712283-G-A is Benign according to our data. Variant chr16-50712283-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97850.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00131 (200/152376) while in subpopulation NFE AF = 0.00201 (137/68028). AF 95% confidence interval is 0.00174. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 200 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.2291G>A	p.Arg764Gln	missense	Exon 4 of 12	NP_001357395.1
	NOD2	NM_022162.3		c.2372G>A	p.Arg791Gln	missense	Exon 4 of 12	NP_071445.1
	NOD2	NM_001293557.2		c.2291G>A	p.Arg764Gln	missense	Exon 3 of 11	NP_001280486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.2291G>A	p.Arg764Gln	missense	Exon 4 of 12	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.2372G>A	p.Arg791Gln	missense	Exon 4 of 12	ENSP00000300589.2
	NOD2	ENST00000534057.1	TSL:1	c.89G>A	p.Arg30Gln	missense	Exon 1 of 5	ENSP00000437246.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152258 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00160 AC: 400 AN: 249550 AF XY: 0.00153

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000979

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00141 AC: 2057 AN: 1461622 Hom.: 4 Cov.: 33 AF XY: 0.00140 AC XY: 1015 AN XY: 727134

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 211 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00103 AC: 55 AN: 53152

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00145 AC: 1616 AN: 1112012

Other (OTH) AF: 0.00164 AC: 99 AN: 60396

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152376 Hom.: 1 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74530

African (AFR) AF: 0.000361 AC: 15 AN: 41598

American (AMR) AF: 0.000849 AC: 13 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00201 AC: 137 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00178 Hom.: 2

Bravo AF: 0.00125

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00156 AC: 189

EpiCase AF: 0.00218

EpiControl AF: 0.00196

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	Inflammatory bowel disease 1 (2)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	Blau syndrome (2)
-	-	1	Regional enteritis;C5201146:Blau syndrome (1)
-	1	-	Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.52
DANN	Benign	0.77
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.12
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.030
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.021	B
Vest4		0.076
MVP		0.25
MPC		0.11
ClinPred		0.0020	T
GERP RS		-5.5
PromoterAI		-0.0046	Neutral
Varity_R		0.041
gMVP		0.17
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs104895464; hg19: chr16-50746194; COSMIC: COSV100319025; COSMIC: COSV100319025;