NM_001370466.1:c.2938dupC

Variant names:

• chr16-50729867-G-GC
• rs2066847
• NM_001370466.1:c.2938dupC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BS1_Supporting BS2

The NM_001370466.1(NOD2):​c.2938dupC​(p.Leu980ProfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,186 control chromosomes in the GnomAD database, including 607 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (30 hom., cov: 32)
  • Exomes 𝑓: 0.018 (577 hom.)
• Consequence: NOD2 NM_001370466.1 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications P:3 U:5 B:6 O:4
• Conservation: PhyloP100: 1.98
• Publications: 375 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]

CYLD-AS1 (HGNC:55352): (CYLD antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0339 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0149 (2274/152284) while in subpopulation NFE AF = 0.0231 (1570/68018). AF 95% confidence interval is 0.0221. There are 30 homozygotes in GnomAd4. There are 1077 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2274 AD,Unknown 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.2938dupC	p.Leu980ProfsTer2	frameshift	Exon 11 of 12	NP_001357395.1
	NOD2	NM_022162.3		c.3019dupC	p.Leu1007ProfsTer2	frameshift	Exon 11 of 12	NP_071445.1
	NOD2	NM_001293557.2		c.2938dupC	p.Leu980ProfsTer2	frameshift	Exon 10 of 11	NP_001280486.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.2938dupC	p.Leu980ProfsTer2	frameshift	Exon 11 of 12	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.3019dupC	p.Leu1007ProfsTer2	frameshift	Exon 11 of 12	ENSP00000300589.2
	NOD2	ENST00000951248.1		c.2938dupC	p.Leu980ProfsTer2	frameshift	Exon 11 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2274 AN: 152166 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0150 AC: 3771 AN: 251370 AF XY: 0.0149

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00845

Gnomad ASJ exome AF: 0.0344

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0185 AC: 26983 AN: 1460902 Hom.: 577 Cov.: 31 AF XY: 0.0182 AC XY: 13198 AN XY: 726788

African (AFR) AF: 0.00236 AC: 79 AN: 33456

American (AMR) AF: 0.00803 AC: 359 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 841 AN: 26098

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86236

European-Finnish (FIN) AF: 0.0147 AC: 784 AN: 53372

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5758

European-Non Finnish (NFE) AF: 0.0215 AC: 23942 AN: 1111282

Other (OTH) AF: 0.0136 AC: 823 AN: 60328

GnomAD4 genome AF: 0.0149 AC: 2274 AN: 152284 Hom.: 30 Cov.: 32 AF XY: 0.0145 AC XY: 1077 AN XY: 74460

African (AFR) AF: 0.00344 AC: 143 AN: 41564

American (AMR) AF: 0.0131 AC: 201 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0231 AC: 1570 AN: 68018

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0854 Hom.: 3249

Bravo AF: 0.0135

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0207

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity; association

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	3	not provided (5)
-	1	1	Blau syndrome (2)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	Crohn disease (1)
-	1	-	Inflammatory bowel disease 1 (3)
-	-	1	not specified (1)
-	1	-	Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 (1)
-	-	-	Crohn disease;C5201146:Blau syndrome (1)
-	-	-	Crohn’s Disease (1)
-	-	-	Regional enteritis;C5201146:Blau syndrome (1)
-	-	-	Yao syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=146/54	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2066847; hg19: chr16-50763778; COSMIC: COSV56054506;