16-50723365-G-A

Variant names:

• chr16-50723365-G-A
• rs5743291
• NM_001370466.1:c.2782G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370466.1(NOD2):​c.2782G>A​(p.Val928Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0772 in 1,613,456 control chromosomes in the GnomAD database, including 5,597 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (390 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5207 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -1.22
• Publications: 65 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=0.0018509626).
• BP6: Variant 16-50723365-G-A is Benign according to our data. Variant chr16-50723365-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0873 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.2782G>A	p.Val928Ile	missense	Exon 9 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2863G>A	p.Val955Ile	missense	Exon 9 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2782G>A	p.Val928Ile	missense	Exon 8 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.2782G>A	p.Val928Ile	missense	Exon 9 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2863G>A	p.Val955Ile	missense	Exon 9 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000534057.1	TSL:1	c.496G>A	p.Val166Ile	missense	Exon 5 of 5	ENSP00000437246.1	H0YF53

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 9154 AN: 152104 Hom.: 390 Cov.: 32

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0658

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0737

Gnomad NFE AF: 0.0892

Gnomad OTH AF: 0.0820

GnomAD2 exomes AF: 0.0627 AC: 15757 AN: 251364 AF XY: 0.0636

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.0510

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.0393

Gnomad NFE exome AF: 0.0885

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0789 AC: 115358 AN: 1461234 Hom.: 5207 Cov.: 31 AF XY: 0.0776 AC XY: 56440 AN XY: 726936

African (AFR) AF: 0.0131 AC: 439 AN: 33476

American (AMR) AF: 0.0524 AC: 2342 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4582 AN: 26122

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39688

South Asian (SAS) AF: 0.0214 AC: 1847 AN: 86234

European-Finnish (FIN) AF: 0.0399 AC: 2128 AN: 53372

Middle Eastern (MID) AF: 0.104 AC: 597 AN: 5768

European-Non Finnish (NFE) AF: 0.0886 AC: 98465 AN: 1111496

Other (OTH) AF: 0.0818 AC: 4939 AN: 60362

GnomAD4 genome AF: 0.0601 AC: 9149 AN: 152222 Hom.: 390 Cov.: 32 AF XY: 0.0562 AC XY: 4180 AN XY: 74428

African (AFR) AF: 0.0165 AC: 684 AN: 41536

American (AMR) AF: 0.0657 AC: 1004 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 619 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4824

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10604

Middle Eastern (MID) AF: 0.0793 AC: 23 AN: 290

European-Non Finnish (NFE) AF: 0.0892 AC: 6064 AN: 68000

Other (OTH) AF: 0.0806 AC: 170 AN: 2108

Alfa AF: 0.0836 Hom.: 2201

Bravo AF: 0.0614

TwinsUK AF: 0.0947 AC: 351

ALSPAC AF: 0.0859 AC: 331

ESP6500AA AF: 0.0162 AC: 71

ESP6500EA AF: 0.0960 AC: 826

ExAC AF: 0.0608 AC: 7387

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0967

EpiControl AF: 0.0987

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.63
DANN	Benign	0.85
DEOGEN2	Benign	0.099	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		-1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.038
Sift	Uncertain	0.027	D
Sift4G	Benign	0.29	T
Polyphen		0.51	P
Vest4		0.035
MPC		0.12
ClinPred		0.0034	T
GERP RS		-6.4
Varity_R		0.017
gMVP		0.080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs5743291; hg19: chr16-50757276; COSMIC: COSV56050718; COSMIC: COSV56050718;