rs104895432

Variant names:

• chr16-50711232-G-A
• rs104895432
• NM_001370466.1:c.1240G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001370466.1(NOD2):​c.1240G>A​(p.Glu414Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,613,998 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). Synonymous variant affecting the same amino acid position (i.e. E414E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 3.38
• Publications: 14 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24522126).
• BP6: Variant 16-50711232-G-A is Benign according to our data. Variant chr16-50711232-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97827.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000341 (52/152344) while in subpopulation AMR AF = 0.000719 (11/15308). AF 95% confidence interval is 0.000402. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 52 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.1240G>A	p.Glu414Lys	missense	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.1321G>A	p.Glu441Lys	missense	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.1240G>A	p.Glu414Lys	missense	Exon 3 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.1240G>A	p.Glu414Lys	missense	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.1321G>A	p.Glu441Lys	missense	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.1240G>A	p.Glu414Lys	missense	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000308 AC: 77 AN: 250350 AF XY: 0.000303

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000505

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000315 AC: 461 AN: 1461654 Hom.: 0 Cov.: 40 AF XY: 0.000315 AC XY: 229 AN XY: 727136

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.000301 AC: 16 AN: 53184

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000364 AC: 405 AN: 1112010

Other (OTH) AF: 0.000397 AC: 24 AN: 60394

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74508

African (AFR) AF: 0.0000962 AC: 4 AN: 41580

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68034

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000464 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.087
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.34
Sift	Benign	0.77	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.38
MVP		0.86
MPC		0.53
ClinPred		0.11	T
GERP RS		4.3
Varity_R		0.099
gMVP		0.69
Mutation Taster		=78/22	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: rs104895432; hg19: chr16-50745143; COSMIC: COSV56049160; COSMIC: COSV56049160;