rs5743278

Variant names:

• chr16-50712085-C-G
• rs5743278
• NM_001370466.1:c.2093C>G

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.2093C>G​(p.Ala698Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,806 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (48 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (55 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.55
• Publications: 25 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=0.0024296641).
• BP6: Variant 16-50712085-C-G is Benign according to our data. Variant chr16-50712085-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319461.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 = 0.0124 (1883/152392) while in subpopulation AFR AF = 0.0433 (1800/41598). AF 95% confidence interval is 0.0416. There are 48 homozygotes in GnomAd4. There are 919 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1883 Unknown,AD 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.2093C>G	p.Ala698Gly	missense	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2174C>G	p.Ala725Gly	missense	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2093C>G	p.Ala698Gly	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.2093C>G	p.Ala698Gly	missense	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2174C>G	p.Ala725Gly	missense	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.2093C>G	p.Ala698Gly	missense	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1881 AN: 152274 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00325 AC: 814 AN: 250736 AF XY: 0.00239

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00143 AC: 2089 AN: 1461414 Hom.: 55 Cov.: 33 AF XY: 0.00123 AC XY: 895 AN XY: 727012

African (AFR) AF: 0.0507 AC: 1697 AN: 33478

American (AMR) AF: 0.00217 AC: 97 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5762

European-Non Finnish (NFE) AF: 0.0000737 AC: 82 AN: 1111948

Other (OTH) AF: 0.00280 AC: 169 AN: 60390

GnomAD4 genome AF: 0.0124 AC: 1883 AN: 152392 Hom.: 48 Cov.: 33 AF XY: 0.0123 AC XY: 919 AN XY: 74526

African (AFR) AF: 0.0433 AC: 1800 AN: 41598

American (AMR) AF: 0.00300 AC: 46 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68044

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00371 Hom.: 3

Bravo AF: 0.0138

ESP6500AA AF: 0.0380 AC: 167

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00402 AC: 488

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Blau syndrome (1)
-	-	1	Inflammatory bowel disease 1 (1)
-	-	1	not specified (1)
-	-	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	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.087
Sift	Benign	0.15	T
Sift4G	Benign	0.26	T
Polyphen		0.010	B
Vest4		0.17
MVP		0.80
MPC		0.11
ClinPred		0.0082	T
GERP RS		3.8
PromoterAI		-0.13	Neutral
Varity_R		0.077
gMVP		0.24
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5743278; hg19: chr16-50745996;