chr16-50712015-C-T

Variant names:

• chr16-50712015-C-T
• rs2066844
• NM_001370466.1:c.2023C>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.2104C>T​(p.Arg702Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,613,122 control chromosomes in the GnomAD database, including 1,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R702Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (111 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1586 hom.)
• Consequence: NOD2 NM_022162.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:4 B:6 O:5
• Conservation: PhyloP100: 0.742
• Publications: 817 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=0.0020624995).
• BP6: Variant 16-50712015-C-T is Benign according to our data. Variant chr16-50712015-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity|association. ClinVar VariationId is 4693.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0284 (4330/152352) while in subpopulation NFE AF = 0.0451 (3065/68026). AF 95% confidence interval is 0.0437. There are 111 homozygotes in GnomAd4. There are 1998 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4330 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.2023C>T	p.Arg675Trp	missense	Exon 4 of 12	NP_001357395.1
	NOD2	NM_022162.3		c.2104C>T	p.Arg702Trp	missense	Exon 4 of 12	NP_071445.1
	NOD2	NM_001293557.2		c.2023C>T	p.Arg675Trp	missense	Exon 3 of 11	NP_001280486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.2023C>T	p.Arg675Trp	missense	Exon 4 of 12	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.2104C>T	p.Arg702Trp	missense	Exon 4 of 12	ENSP00000300589.2
	NOD2	ENST00000951248.1		c.2023C>T	p.Arg675Trp	missense	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4330 AN: 152234 Hom.: 111 Cov.: 33

Gnomad AFR AF: 0.00854

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0451

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0261 AC: 6476 AN: 248574 AF XY: 0.0262

Gnomad AFR exome AF: 0.00699

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.0433

Gnomad OTH exome AF: 0.0304

GnomAD4 exome AF: 0.0396 AC: 57781 AN: 1460770 Hom.: 1586 Cov.: 34 AF XY: 0.0383 AC XY: 27842 AN XY: 726726

African (AFR) AF: 0.00654 AC: 219 AN: 33478

American (AMR) AF: 0.0216 AC: 967 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 542 AN: 26110

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86234

European-Finnish (FIN) AF: 0.0182 AC: 957 AN: 52572

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5762

European-Non Finnish (NFE) AF: 0.0478 AC: 53173 AN: 1111848

Other (OTH) AF: 0.0309 AC: 1863 AN: 60362

GnomAD4 genome AF: 0.0284 AC: 4330 AN: 152352 Hom.: 111 Cov.: 33 AF XY: 0.0268 AC XY: 1998 AN XY: 74496

African (AFR) AF: 0.00851 AC: 354 AN: 41590

American (AMR) AF: 0.0321 AC: 492 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0451 AC: 3065 AN: 68026

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0411 Hom.: 346

Bravo AF: 0.0299

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.00820 AC: 36

ESP6500EA AF: 0.0435 AC: 374

ExAC AF: 0.0226 AC: 2743

EpiCase AF: 0.0470

EpiControl AF: 0.0418

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity; association

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Blau syndrome (3)
-	-	2	not provided (2)
-	1	1	not specified (2)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	Inflammatory bowel disease 1 (2)
-	1	-	Yao syndrome (2)
-	-	1	Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 (1)
-	-	-	Crohn disease (1)
-	-	-	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.0062
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.74
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.046
MPC		0.10
ClinPred		0.025	T
GERP RS		3.7
PromoterAI		0.037	Neutral
Varity_R		0.18
gMVP		0.48
Mutation Taster		=97/3	polymorphism (auto)

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: rs2066844; hg19: chr16-50745926; COSMIC: COSV107363615; COSMIC: COSV107363615;