NM_001370466.1:c.2288G>A

Variant names:

• chr16-50712280-G-A
• rs5743279
• NM_001370466.1:c.2288G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001370466.1(NOD2):​c.2288G>A​(p.Arg763Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,613,954 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R763W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0095 (27 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (19 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.158
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034513175).
• BP6: Variant 16-50712280-G-A is Benign according to our data. Variant chr16-50712280-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00951 (1449/152360) while in subpopulation AFR AF = 0.0333 (1386/41586). AF 95% confidence interval is 0.0319. There are 27 homozygotes in GnomAd4. There are 651 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1449 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.2288G>A	p.Arg763Gln	missense	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2369G>A	p.Arg790Gln	missense	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2288G>A	p.Arg763Gln	missense	Exon 3 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.2288G>A	p.Arg763Gln	missense	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2369G>A	p.Arg790Gln	missense	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000534057.1	TSL:1	c.86G>A	p.Arg29Gln	missense	Exon 1 of 5	ENSP00000437246.1	H0YF53

Frequencies

GnomAD3 genomes AF: 0.00950 AC: 1447 AN: 152242 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00238 AC: 595 AN: 249636 AF XY: 0.00173

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000941 AC: 1375 AN: 1461594 Hom.: 19 Cov.: 33 AF XY: 0.000805 AC XY: 585 AN XY: 727112

African (AFR) AF: 0.0339 AC: 1136 AN: 33480

American (AMR) AF: 0.00186 AC: 83 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53122

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1112012

Other (OTH) AF: 0.00194 AC: 117 AN: 60396

GnomAD4 genome AF: 0.00951 AC: 1449 AN: 152360 Hom.: 27 Cov.: 33 AF XY: 0.00874 AC XY: 651 AN XY: 74518

African (AFR) AF: 0.0333 AC: 1386 AN: 41586

American (AMR) AF: 0.00255 AC: 39 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00412 Hom.: 11

Bravo AF: 0.0109

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0339 AC: 149

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00296 AC: 359

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.3
DANN	Benign	0.70
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L
PhyloP100		0.16
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.017
Sift	Benign	0.58	T
Sift4G	Benign	0.44	T
Polyphen		0.17	B
Vest4		0.099
MVP		0.40
MPC		0.11
ClinPred		0.0021	T
GERP RS		-0.17
PromoterAI		-0.022	Neutral
Varity_R		0.033
gMVP		0.16
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs5743279; hg19: chr16-50746191;