rs104895456

Variant names:

• chr16-50699827-G-A
• rs104895456
• NM_001370466.1:c.332G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001370466.1(NOD2):​c.332G>A​(p.Arg111Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R111W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3 O:1
• Conservation: PhyloP100: 5.54
• Publications: 8 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16849265).
• BP6: Variant 16-50699827-G-A is Benign according to our data. Variant chr16-50699827-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97877.
• BS2: High AC in GnomAd4 at 14 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.332G>A	p.Arg111Gln	missense	Exon 2 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.413G>A	p.Arg138Gln	missense	Exon 2 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.332G>A	p.Arg111Gln	missense	Exon 1 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.332G>A	p.Arg111Gln	missense	Exon 2 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.413G>A	p.Arg138Gln	missense	Exon 2 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000527070.5	TSL:1	c.332G>A	p.Arg111Gln	missense	Exon 2 of 4	ENSP00000435149.2	E9PLF7

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000758 AC: 19 AN: 250786 AF XY: 0.0000885

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1461264 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 98 AN XY: 726928

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000171 AC: 190 AN: 1111934

Other (OTH) AF: 0.000265 AC: 16 AN: 60390

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74470

African (AFR) AF: 0.000120 AC: 5 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Blau syndrome (2)
-	-	1	Inflammatory bowel disease 1 (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	Uncertain	0.42
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.5
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.17
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.73	P
Vest4		0.52
MVP		0.79
MPC		0.36
ClinPred		0.37	T
GERP RS		5.3
Varity_R		0.22
gMVP		0.74
Mutation Taster		=65/35	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: rs104895456; hg19: chr16-50733738;