rs61755182

Variant names:

• chr16-50707880-C-T
• rs61755182
• NM_001370466.1:c.485C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022162.3(NOD2):​c.566C>T​(p.Thr189Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,613,890 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T189T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: NOD2 NM_022162.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.69
• Publications: 23 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: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• inflammatory bowel disease 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008413136).
• BP6: Variant 16-50707880-C-T is Benign according to our data. Variant chr16-50707880-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 319431.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00274 (417/152290) while in subpopulation NFE AF = 0.00435 (296/68032). AF 95% confidence interval is 0.00394. There are 0 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 417 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022162.3. 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.485C>T	p.Thr162Met	missense	Exon 3 of 12	NP_001357395.1
	NOD2	NM_022162.3		c.566C>T	p.Thr189Met	missense	Exon 3 of 12	NP_071445.1
	NOD2	NM_001293557.2		c.485C>T	p.Thr162Met	missense	Exon 2 of 11	NP_001280486.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.485C>T	p.Thr162Met	missense	Exon 3 of 12	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.566C>T	p.Thr189Met	missense	Exon 3 of 12	ENSP00000300589.2
	NOD2	ENST00000527070.5	TSL:1	c.485C>T	p.Thr162Met	missense	Exon 3 of 4	ENSP00000435149.2

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00225 AC: 565 AN: 251492 AF XY: 0.00219

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00304 AC: 4449 AN: 1461600 Hom.: 7 Cov.: 31 AF XY: 0.00295 AC XY: 2148 AN XY: 727118

African (AFR) AF: 0.00149 AC: 50 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

European-Finnish (FIN) AF: 0.00154 AC: 82 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00372 AC: 4136 AN: 1111748

Other (OTH) AF: 0.00229 AC: 138 AN: 60394

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00251 AC XY: 187 AN XY: 74460

African (AFR) AF: 0.00171 AC: 71 AN: 41550

American (AMR) AF: 0.000849 AC: 13 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 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: 0.00179 AC: 19 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00435 AC: 296 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00391 Hom.: 7

Bravo AF: 0.00255

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00259 AC: 315

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	1	Inflammatory bowel disease 1 (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Blau syndrome (1)
-	-	1	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.039
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.25
MVP		0.84
MPC		0.47
ClinPred		0.022	T
GERP RS		3.6
Varity_R		0.041
gMVP		0.30
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: rs61755182; hg19: chr16-50741791; COSMIC: COSV99039070; COSMIC: COSV99039070;