16-50722681-A-G

Variant names:

• chr16-50722681-A-G
• rs545734771
• NM_001370466.1:c.2693A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001370466.1(NOD2):​c.2693A>G​(p.Asp898Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.28
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053600997).
• BS2: High AC in GnomAd4 at 11 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.2693A>G	p.Asp898Gly	missense	Exon 8 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2774A>G	p.Asp925Gly	missense	Exon 8 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2693A>G	p.Asp898Gly	missense	Exon 7 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.2693A>G	p.Asp898Gly	missense	Exon 8 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2774A>G	p.Asp925Gly	missense	Exon 8 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000534057.1	TSL:1	c.407A>G	p.Asp136Gly	missense	Exon 4 of 5	ENSP00000437246.1	H0YF53

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000437 AC: 11 AN: 251474 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112008

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74504

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	NOD2-related disorder (1)
-	1	-	not specified (1)
-	1	-	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.035	N
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.18	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.31		Loss of helix (P = 0.0376)
MVP		0.80
MPC		0.13
ClinPred		0.054	T
GERP RS		3.7
Varity_R		0.071
gMVP		0.22
Mutation Taster		=97/3	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: rs545734771; hg19: chr16-50756592;