rs1861759

Variant names:

• chr16-50711672-T-G
• rs1861759
• NM_001370466.1:c.1680T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001370466.1(NOD2):​c.1680T>G​(p.Arg560Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,612,716 control chromosomes in the GnomAD database, including 111,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8582 hom., cov: 33)
  • Exomes 𝑓: 0.37 (103051 hom.)
• Consequence: NOD2 NM_001370466.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -1.55
• Publications: 53 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-50711672-T-G is Benign according to our data. Variant chr16-50711672-T-G is described in ClinVar as Benign. ClinVar VariationId is 319450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

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.1680T>G	p.Arg560Arg	synonymous	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.1761T>G	p.Arg587Arg	synonymous	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.1680T>G	p.Arg560Arg	synonymous	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.1680T>G	p.Arg560Arg	synonymous	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.1761T>G	p.Arg587Arg	synonymous	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.1680T>G	p.Arg560Arg	synonymous	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48660 AN: 152050 Hom.: 8585 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.334

GnomAD2 exomes AF: 0.329 AC: 82175 AN: 249426 AF XY: 0.331

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.531

Gnomad EAS exome AF: 0.106

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.367 AC: 536574 AN: 1460548 Hom.: 103051 Cov.: 66 AF XY: 0.365 AC XY: 264896 AN XY: 726538

African (AFR) AF: 0.190 AC: 6368 AN: 33476

American (AMR) AF: 0.283 AC: 12619 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 14064 AN: 26130

East Asian (EAS) AF: 0.126 AC: 4983 AN: 39654

South Asian (SAS) AF: 0.232 AC: 20022 AN: 86206

European-Finnish (FIN) AF: 0.400 AC: 21109 AN: 52772

Middle Eastern (MID) AF: 0.385 AC: 2217 AN: 5764

European-Non Finnish (NFE) AF: 0.390 AC: 433666 AN: 1111560

Other (OTH) AF: 0.357 AC: 21526 AN: 60358

GnomAD4 genome AF: 0.320 AC: 48665 AN: 152168 Hom.: 8582 Cov.: 33 AF XY: 0.315 AC XY: 23452 AN XY: 74398

African (AFR) AF: 0.194 AC: 8061 AN: 41518

American (AMR) AF: 0.318 AC: 4862 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1859 AN: 3470

East Asian (EAS) AF: 0.104 AC: 537 AN: 5176

South Asian (SAS) AF: 0.205 AC: 991 AN: 4826

European-Finnish (FIN) AF: 0.399 AC: 4216 AN: 10576

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26955 AN: 67978

Other (OTH) AF: 0.329 AC: 697 AN: 2116

Alfa AF: 0.368 Hom.: 7313

Bravo AF: 0.312

Asia WGS AF: 0.163 AC: 564 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (3)
-	-	1	Blau syndrome (1)
-	-	1	Inflammatory bowel disease 1 (1)
-	-	1	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.28
DANN	Benign	0.42
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs1861759; hg19: chr16-50745583; COSMIC: COSV56050793; COSMIC: COSV56050793;